Secreted and transmembrane polypeptides and nucleic acids encoding the same

ABSTRACT

The present invention is directed to novel polypeptides and to nucleic acid molecules encoding those polypeptides. Also provided herein are vectors and host cells comprising those nucleic acid sequences, chimeric polypeptide molecules comprising the polypeptides of the present invention fused to heterologous polypeptide sequences, antibodies which bind to the polypeptides of the present invention and to methods for producing the polypeptides of the present invention.

FIELD OF THE INVENTION

[0001] The present invention relates generally to the identification andisolation of novel DNA and to the recombinant production of novelpolypeptides.

BACKGROUND OF THE INVENTION

[0002] Extracellular proteins play important roles in, among otherthings, the formation, differentiation and maintenance of multicellularorganisms. The fate of many individual cells, e.g., proliferation,migration, differentiation, or interaction with other cells, istypically governed by information received from other cells and/or theimmediate environment. This information is often transmitted by secretedpolypeptides (for instance, mitogenic factors, survival factors,cytotoxic factors, differentiation factors, neuropeptides, and hormones)which are, in turn, received and interpreted by diverse cell receptorsor membrane-bound proteins. These secreted polypeptides or signalingmolecules normally pass through the cellular secretory pathway to reachtheir site of action in the extracellular environment.

[0003] Secreted proteins have various industrial applications, includingas pharmaceuticals, diagnostics, biosensors and bioreactors. Mostprotein drugs available at present, such as thrombolytic agents,interferons, interleukins, erythropoietins, colony stimulating factors,and various other cytokines, are secretory proteins. Their receptors,which are membrane proteins, also have potential as therapeutic ordiagnostic agents. Efforts are being undertaken by both industry andacademia to identify new, native secreted proteins. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel secreted proteins. Examples ofscreening methods and techniques are described in the literature [see,for example, Klein et al., Proc. Natl. Acad. Sci. 93:7108-7113 (1996);U.S. Pat. No. 5,536,637)].

[0004] Membrane-bound proteins and receptors can play important rolesin, among other things, the formation, differentiation and maintenanceof multicellular organisms. The fate of many individual cells, e.g.,proliferation, migration, differentiation, or interaction with othercells, is typically governed by information received from other cellsand/or the immediate environment. This information is often transmittedby secreted polypeptides (for instance, mitogenic factors, survivalfactors, cytotoxic factors, differentiation factors, neuropeptides, andhormones) which are, in turn, received and interpreted by diverse cellreceptors or membrane-bound proteins. Such membrane-bound proteins andcell receptors include, but are not limited to, cytokine receptors,receptor kinases, receptor phosphatases, receptors involved in cell-cellinteractions, and cellular adhesin molecules like selectins andintegrins. For instance, transduction of signals that regulate cellgrowth and differentiation is regulated in part by phosphorylation ofvarious cellular proteins. Protein tyrosine kinases, enzymes thatcatalyze that process, can also act as growth factor receptors. Examplesinclude fibroblast growth factor receptor and nerve growth factorreceptor.

[0005] Membrane-bound proteins and receptor molecules have variousindustrial applications, including as pharmaceutical and diagnosticagents. Receptor immunoadhesins, for instance, can be employed astherapeutic agents to block receptor-ligand interactions. Themembrane-bound proteins can also be employed for screening of potentialpeptide or small molecule inhibitors of the relevant receptor/ligandinteraction.

[0006] Efforts are being undertaken by both industry and academia toidentify new, native receptor or membrane-bound proteins. Many effortsare focused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel receptor or membrane-boundproteins.

SUMMARY OF THE INVENTION

[0007] In one embodiment, the invention provides an isolated nucleicacid molecule comprising a nucleotide sequence that encodes a PROpolypeptide.

[0008] In one aspect, the isolated nucleic acid molecule comprises anucleotide sequence having at least about 80% nucleic acid sequenceidentity, alternatively at least about 81% nucleic acid sequenceidentity, alternatively at least about 82% nucleic acid sequenceidentity, alternatively at least about 83% nucleic acid sequenceidentity, alternatively at least about 84% nucleic acid sequenceidentity, alternatively at least about 85% nucleic acid sequenceidentity, alternatively at least about 86% nucleic acid sequenceidentity, alternatively at least about 87% nucleic acid sequenceidentity, alternatively at least about 88% nucleic acid sequenceidentity, alternatively at least about 89% nucleic acid sequenceidentity, alternatively at least about 90% nucleic acid sequenceidentity, alternatively at least about 91% nucleic acid sequenceidentity, alternatively at least about 92% nucleic acid sequenceidentity, alternatively at least about 93% nucleic acid sequenceidentity, alternatively at least about 94% nucleic acid sequenceidentity, alternatively at least about 95% nucleic acid sequenceidentity, alternatively at least about 96% nucleic acid sequenceidentity, alternatively at least about 97% nucleic acid sequenceidentity, alternatively at least about 98% nucleic acid sequenceidentity and alternatively at least about 99% nucleic acid sequenceidentity to (a) a DNA molecule encoding a PRO polypeptide having afull-length amino acid sequence as disclosed herein, an amino acidsequence lacking the signal peptide as disclosed herein, anextracellular domain of a transmembrane protein, with or without thesignal peptide, as disclosed herein or any other specifically definedfragment of the full-length amino acid sequence as disclosed herein, or(b) the complement of the DNA molecule of (a).

[0009] In other aspects, the isolated nucleic acid molecule comprises anucleotide sequence having at least about 80% nucleic acid sequenceidentity, alternatively at least about 81% nucleic acid sequenceidentity, alternatively at least about 82% nucleic acid sequenceidentity, alternatively at least about 83% nucleic acid sequenceidentity, alternatively at least about 84% nucleic acid sequenceidentity, alternatively at least about 85% nucleic acid sequenceidentity, alternatively at least about 86% nucleic acid sequenceidentity, alternatively at least about 87% nucleic acid sequenceidentity, alternatively at least about 88% nucleic acid sequenceidentity, alternatively at least about 89% nucleic acid sequenceidentity, alternatively at least about 90% nucleic acid sequenceidentity, alternatively at least about 91% nucleic acid sequenceidentity, alternatively at least about 92% nucleic acid sequenceidentity, alternatively at least about 93% nucleic acid sequenceidentity, alternatively at least about 94% nucleic acid sequenceidentity, alternatively at least about 95% nucleic acid sequenceidentity, alternatively at least about 96% nucleic acid sequenceidentity, alternatively at least about 97% nucleic acid sequenceidentity, alternatively at least about 98% nucleic acid sequenceidentity and alternatively at least about 99% nucleic acid sequenceidentity to (a) a DNA molecule comprising the coding sequence of afull-length PRO polypeptide cDNA as disclosed herein, the codingsequence of a PRO polypeptide lacking the signal peptide as disclosedherein, the coding sequence of an extracellular domain of atransmembrane PRO polypeptide, with or without the signal peptide, asdisclosed herein or the coding sequence of any other specificallydefined fragment of the full-length amino acid sequence as disclosedherein, or (b) the complement of the DNA molecule of (a).

[0010] In a further aspect, the invention concerns an isolated nucleicacid molecule comprising a nucleotide sequence having at least about 80%nucleic acid sequence identity, alternatively at least about 81% nucleicacid sequence identity, alternatively at least about 82% nucleic acidsequence identity, alternatively at least about 83% nucleic acidsequence identity, alternatively at least about 84% nucleic acidsequence identity, alternatively at least about 85% nucleic acidsequence identity, alternatively at least about 86% nucleic acidsequence identity, alternatively at least about 87% nucleic acidsequence identity, alternatively at least about 88% nucleic acidsequence identity, alternatively at least about 89% nucleic acidsequence identity, alternatively at least about 90% nucleic acidsequence identity, alternatively at least about 91% nucleic acidsequence identity, alternatively at least about 92% nucleic acidsequence identity, alternatively at least about 93% nucleic acidsequence identity, alternatively at least about 94% nucleic acidsequence identity, alternatively at least about 95% nucleic acidsequence identity, alternatively at least about 96% nucleic acidsequence identity, alternatively at least about 97% nucleic acidsequence identity, alternatively at least about 98% nucleic acidsequence identity and alternatively at least about 99% nucleic acidsequence identity to (a) a DNA molecule that encodes the same maturepolypeptide encoded by any of the human protein cDNAs deposited with theATCC as disclosed herein, or (b) the complement of the DNA molecule of(a).

[0011] Another aspect the invention provides an isolated nucleic acidmolecule comprising a nucleotide sequence encoding a PRO polypeptidewhich is either transmembrane domain-deleted or transmembranedomain-inactivated, or is complementary to such encoding nucleotidesequence, wherein the transmembrane domain(s) of such polypeptide aredisclosed herein. Therefore, soluble extracellular domains of the hereindescribed PRO polypeptides are contemplated.

[0012] Another embodiment is directed to fragments of a PRO polypeptidecoding sequence, or the complement thereof, that may find use as, forexample, hybridization probes, for encoding fragments of a PROpolypeptide that may optionally encode a polypeptide comprising abinding site for an anti-PRO antibody or as antisense oligonucleotideprobes. Such nucleic acid fragments are usually at least about 10nucleotides in length, alternatively at least about 15 nucleotides inlength, alternatively at least about 20 nucleotides in length,alternatively at least about 30 nucleotides in length, alternatively atleast about 40 nucleotides in length, alternatively at least about 50nucleotides in length, alternatively at least about 60 nucleotides inlength, alternatively at least about 70 nucleotides in length,alternatively at least about 80 nucleotides in length, alternatively atleast about 90 nucleotides in length, alternatively at least about 100nucleotides in length, alternatively at least about 110 nucleotides inlength, alternatively at least about 120 nucleotides in length,alternatively at least about 130 nucleotides in length, alternatively atleast about 140 nucleotides in length, alternatively at least about 150nucleotides in length, alternatively at least about 160 nucleotides inlength, alternatively at least about 170 nucleotides in length,alternatively at least about 180 nucleotides in length, alternatively atleast about 190 nucleotides in length, alternatively at least about 200nucleotides in length, alternatively at least about 250 nucleotides inlength, alternatively at least about 300 nucleotides in length,alternatively at least about 350 nucleotides in length, alternatively atleast about 400 nucleotides in length, alternatively at least about 450nucleotides in length, alternatively at least about 500 nucleotides inlength, alternatively at least about 600 nucleotides in length,alternatively at least about 700 nucleotides in length, alternatively atleast about 800 nucleotides in length, alternatively at least about 900nucleotides in length and alternatively at least about 1000 nucleotidesin length, wherein in this context the term “about” means the referencednucleotide sequence length plus or minus 10% of that referenced length.It is noted that novel fragments of a PRO polypeptide-encodingnucleotide sequence may be determined in a routine manner by aligningthe PRO polypeptide-encoding nucleotide sequence with other knownnucleotide sequences using any of a number of well known sequencealignment programs and determining which PRO polypeptide-encodingnucleotide sequence fragment(s) are novel. All of such PROpolypeptide-encoding nucleotide sequences are contemplated herein. Alsocontemplated are the PRO polypeptide fragments encoded by thesenucleotide molecule fragments, preferably those PRO polypeptidefragments that comprise a binding site for an anti-PRO antibody.

[0013] In another embodiment, the invention provides isolated PROpolypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

[0014] In a certain aspect, the invention concerns an isolated PROpolypeptide, comprising an amino acid sequence having at least about 80%amino acid sequence identity, alternatively at least about 81% aminoacid sequence identity, alternatively at least about 82% amino acidsequence identity, alternatively at least about 83% amino acid sequenceidentity, alternatively at least about 84% amino acid sequence identity,alternatively at least about 85% amino acid sequence identity,alternatively at least about 86% amino acid sequence identity,alternatively at least about 87% amino acid sequence identity,alternatively at least about 88% amino acid sequence identity,alternatively at least about 89% amino acid sequence identity,alternatively at least about 90% amino acid sequence identity,alternatively at least about 91% amino acid sequence identity,alternatively at least about 92% amino acid sequence identity,alternatively at least about 93% amino acid sequence identity,alternatively at least about 94% amino acid sequence identity,alternatively at least about 95% amino acid sequence identity,alternatively at least about 96% amino acid sequence identity,alternatively at least about 97% amino acid sequence identity,alternatively at least about 98% amino acid sequence identity andalternatively at least about 99% amino acid sequence identity to a PROpolypeptide having a full-length amino acid sequence as disclosedherein, an amino acid sequence lacking the signal peptide as disclosedherein, an extracellular domain of a transmembrane protein, with orwithout the signal peptide, as disclosed herein or any otherspecifically defined fragment of the full-length amino acid sequence asdisclosed herein.

[0015] In a further aspect, the invention concerns an isolated PROpolypeptide comprising an amino acid sequence having at least about 80%amino acid sequence identity, alternatively at least about 81% aminoacid sequence identity, alternatively at least about 82% amino acidsequence identity, alternatively at least about 83% amino acid sequenceidentity, alternatively at least about 84% amino acid sequence identity,alternatively at least about 85% amino acid sequence identity,alternatively at least about 86% amino acid sequence identity,alternatively at least about 87% amino acid sequence identity,alternatively at least about 88% amino acid sequence identity,alternatively at least about 89% amino acid sequence identity,alternatively at least about 90% amino acid sequence identity,alternatively at least about 91% amino acid sequence identity,alternatively at least about 92% amino acid sequence identity,alternatively at least about 93% amino acid sequence identity,alternatively at least about 94% amino acid sequence identity,alternatively at least about 95% amino acid sequence identity,alternatively at least about 96% amino acid sequence identity,alternatively at least about 97% amino acid sequence identity,alternatively at least about 98% amino acid sequence identity andalternatively at least about 99% amino acid sequence identity to anamino acid sequence encoded by any of the human protein cDNAs depositedwith the ATCC as disclosed herein.

[0016] In a specific aspect, the invention provides an isolated PROpolypeptide without the N-terminal signal sequence and/or the initiatingmethionine and is encoded by a nucleotide sequence that encodes such anamino acid sequence as hereinbefore described. Processes for producingthe same are also herein described, wherein those processes compriseculturing a host cell comprising a vector which comprises theappropriate encoding nucleic acid molecule under conditions suitable forexpression of the PRO polypeptide and recovering the PRO polypeptidefrom the cell culture.

[0017] Another aspect the invention provides an isolated PRO polypeptidewhich is either transmembrane domain-deleted or transmembranedomain-inactivated. Processes for producing the same are also hereindescribed, wherein those processes comprise culturing a host cellcomprising a vector which comprises the appropriate encoding nucleicacid molecule under conditions suitable for expression of the PROpolypeptide and recovering the PRO polypeptide from the cell culture.

[0018] In yet another embodiment, the invention concerns agonists andantagonists of a native PRO polypeptide as defined herein. In aparticular embodiment, the agonist or antagonist is an anti-PRO antibodyor a small molecule.

[0019] In a further embodiment, the invention concerns a method ofidentifying agonists or antagonists to a PRO polypeptide which comprisecontacting the PRO polypeptide with a candidate molecule and monitoringa biological activity mediated by said PRO polypeptide. Preferably, thePRO polypeptide is a native PRO polypeptide.

[0020] In a still further embodiment, the invention concerns acomposition of matter comprising a PRO polypeptide, or an agonist orantagonist of a PRO polypeptide as herein described, or an anti-PROantibody, in combination with a carrier. Optionally, the carrier is apharmaceutically acceptable carrier.

[0021] Another embodiment of the present invention is directed to theuse of a PRO polypeptide, or an agonist or antagonist thereof ashereinbefore described, or an anti-PRO antibody, for the preparation ofa medicament useful in the treatment of a condition which is responsiveto the PRO polypeptide, an agonist or antagonist thereof or an anti-PROantibody.

[0022] In other embodiments of the present invention, the inventionprovides vectors comprising DNA encoding any of the herein describedpolypeptides. Host cell comprising any such vector are also provided. Byway of example, the host cells may be CHO cells, E. coli, or yeast. Aprocess for producing any of the herein described polypeptides isfurther provided and comprises culturing host cells under conditionssuitable for expression of the desired polypeptide and recovering thedesired polypeptide from the cell culture.

[0023] In other embodiments, the invention provides chimeric moleculescomprising any of the herein described polypeptides fused to aheterologous polypeptide or amino acid sequence. Example of suchchimeric molecules comprise any of the herein described polypeptidesfused to an epitope tag sequence or a Fc region of an immunoglobulin.

[0024] In another embodiment, the invention provides an antibody whichbinds, preferably specifically, to any of the above or below describedpolypeptides. Optionally, the antibody is a monoclonal antibody,humanized antibody, antibody fragment or single-chain antibody.

[0025] In yet other embodiments, the invention provides oligonucleotideprobes which may be useful for isolating genomic and cDNA nucleotidesequences, measuring or detecting expression of an associated gene or asantisense probes, wherein those probes may be derived from any of theabove or below described nucleotide sequences. Preferred probe lengthsare described above.

[0026] In yet other embodiments, the present invention is directed tomethods of using the PRO polypeptides of the present invention for avariety of uses based upon the functional biological assay datapresented in the Examples below.

BRIEF DESCRIPTION OF THE DRAWINGS

[0027]FIG. 1 shows a nucleotide sequence (SEQ ID NO:1) of a nativesequence PRO281 cDNA, wherein SEQ ID NO:1 is a clone designated hereinas “DNA16422-1209”.

[0028]FIG. 2 shows the amino acid sequence (SEQ ID NO:2) derived fromthe coding sequence of SEQ ID NO:1 shown in FIG. 1.

[0029]FIG. 3 shows a nucleotide sequence (SEQ ID NO:3) of a nativesequence PRO1560 cDNA, wherein SEQ ID NO:3 is a clone designated hereinas “DNA19902-1669”.

[0030]FIG. 4 shows the amino acid sequence (SEQ ID NO:4) derived fromthe coding sequence of SEQ ID NO:3 shown in FIG. 3.

[0031]FIG. 5 shows a nucleotide sequence (SEQ ID NO:5) of a nativesequence PRO189 cDNA, wherein SEQ ID NO:5 is a clone designated hereinas “DNA21624-1391”.

[0032]FIG. 6 shows the amino acid sequence (SEQ ID NO:6) derived fromthe coding sequence of SEQ ID NO:5 shown in FIG. 5.

[0033]FIG. 7 shows a nucleotide sequence (SEQ ID NO:7) of a nativesequence PRO240 cDNA, wherein SEQ ID NO:7 is a clone designated hereinas “DNA34387-1138”.

[0034]FIG. 8 shows the amino acid sequence (SEQ ID NO:8) derived fromthe coding sequence of SEQ ID NO:7 shown in FIG. 7.

[0035]FIG. 9 shows a nucleotide sequence (SEQ ID NO:9) of a nativesequence PRO256 cDNA, wherein SEQ ID NO:9 is a clone designated hereinas “DNA35880-1160”.

[0036]FIG. 10 shows the amino acid sequence (SEQ ID NO:10) derived fromthe coding sequence of SEQ ID NO:9 shown in FIG. 9.

[0037]FIG. 11 shows a nucleotide sequence (SEQ ID NO:11) of a nativesequence PRO306 cDNA, wherein SEQ ID NO:11 is a clone designated hereinas “DNA39984-1221”.

[0038]FIG. 12 shows the amino acid sequence (SEQ ID NO:12) derived fromthe coding sequence of SEQ ID NO:11 shown in FIG. 11.

[0039]FIG. 13 shows a nucleotide sequence (SEQ ID NO:13) of a nativesequence PRO540 cDNA, wherein SEQ ID NO:13 is a clone designated hereinas “DNA44189-1322”.

[0040]FIG. 14 shows the amino acid sequence (SEQ ID NO:14) derived fromthe coding sequence of SEQ ID NO:13 shown in FIG. 13.

[0041]FIG. 15 shows a nucleotide sequence (SEQ ID NO:15) of a nativesequence PRO773 cDNA, wherein SEQ ID NO:15 is a clone designated hereinas “DNA48303-2829”.

[0042]FIG. 16 shows the amino acid sequence (SEQ ID NO:16) derived fromthe coding sequence of SEQ ID NO:15 shown in FIG. 15.

[0043]FIG. 17 shows a nucleotide sequence (SEQ ID NO:17) of a nativesequence PRO698 cDNA, wherein SEQ ID NO:17 is a clone designated hereinas “DNA48320-1433”.

[0044]FIG. 18 shows the amino acid sequence (SEQ ID NO:18) derived fromthe coding sequence of SEQ ID NO:17 shown in FIG. 17.

[0045]FIG. 19 shows a nucleotide sequence (SEQ ID NO:19) of a nativesequence PRO3567 cDNA, wherein SEQ ID NO:19 is a clone designated hereinas “DNA56049-2543”.

[0046]FIG. 20 shows the amino acid sequence (SEQ ID NO:20) derived fromthe coding sequence of SEQ ID NO:19 shown in FIG. 19.

[0047]FIG. 21 shows a nucleotide sequence (SEQ ID NO:21) of a nativesequence PRO826 cDNA, wherein SEQ ID NO:21 is a clone designated hereinas “DNA57694-1341”.

[0048]FIG. 22 shows the amino acid sequence (SEQ ID NO:22) derived fromthe coding sequence of SEQ ID NO:21 shown in FIG. 21.

[0049]FIG. 23 shows a nucleotide sequence (SEQ ID NO:23) of a nativesequence PRO1002 cDNA, wherein SEQ ID NO:23 is a clone designated hereinas “DNA59208-1373”.

[0050]FIG. 24 shows the amino acid sequence (SEQ ID NO:24) derived fromthe coding sequence of SEQ ID NO:23 shown in FIG. 23.

[0051]FIG. 25 shows a nucleotide sequence (SEQ ID NO:25) of a nativesequence PRO1068 cDNA, wherein SEQ ID NO:25 is a clone designated hereinas “DNA59214-1449”.

[0052]FIG. 26 shows the amino acid sequence (SEQ ID NO:26) derived fromthe coding sequence of SEQ ID NO:25 shown in FIG. 25.

[0053]FIG. 27 shows a nucleotide sequence (SEQ ID NO:27) of a nativesequence PRO1030 cDNA, wherein SEQ ID NO:27 is a clone designated hereinas “DNA59485-1336”.

[0054]FIG. 28 shows the amino acid sequence (SEQ ID NO:28) derived fromthe coding sequence of SEQ ID NO:27 shown in FIG. 27.

[0055]FIG. 29 shows a nucleotide sequence (SEQ ID NO:29) of a nativesequence PRO1313 cDNA, wherein SEQ ID NO:29 is a clone designated hereinas “DNA64966-1575”.

[0056]FIG. 30 shows the amino acid sequence (SEQ ID NO:30) derived fromthe coding sequence of SEQ ID NO:29 shown in FIG. 29.

[0057]FIG. 31 shows a nucleotide sequence (SEQ ID NO:31) of a nativesequence PRO6071 cDNA, wherein SEQ ID NO:31 is a clone designated hereinas “DNA82403-2959”.

[0058]FIG. 32 shows the amino acid sequence (SEQ ID NO:32) derived fromthe coding sequence of SEQ ID NO:31 shown in FIG. 31.

[0059]FIG. 33 shows a nucleotide sequence (SEQ ID NO:33) of a nativesequence PRO4397 cDNA, wherein SEQ ID NO:33 is a clone designated hereinas “DNA83505-2606”.

[0060]FIG. 34 shows the amino acid sequence (SEQ ID NO:34) derived fromthe coding sequence of SEQ ID NO:33 shown in FIG. 33.

[0061]FIG. 35 shows a nucleotide sequence (SEQ ID NO:35) of a nativesequence PRO4344 cDNA, wherein SEQ ID NO:35 is a clone designated hereinas “DNA84927-2585”.

[0062]FIG. 36 shows the amino acid sequence (SEQ ID NO:36) derived fromthe coding sequence of SEQ ID NO:35 shown in FIG. 35.

[0063]FIG. 37 shows a nucleotide sequence (SEQ ID NO:37) of a nativesequence PRO4407 cDNA, wherein SEQ ID NO:37 is a clone designated hereinas “DNA92264-2616”.

[0064]FIG. 38 shows the amino acid sequence (SEQ ID NO:38) derived fromthe coding sequence of SEQ ID NO:37 shown in FIG. 37.

[0065]FIG. 39 shows a nucleotide sequence (SEQ ID NO:39) of a nativesequence PRO4316 cDNA, wherein SEQ ID NO:39 is a clone designated hereinas “DNA94713-2561”.

[0066]FIG. 40 shows the amino acid sequence (SEQ ID NO:40) derived fromthe coding sequence of SEQ ID NO:39 shown in FIG. 39.

[0067]FIG. 41 shows a nucleotide sequence (SEQ ID NO:41) of a nativesequence PRO5775 cDNA, wherein SEQ ID NO:41 is a clone designated hereinas “DNA96869-2673”.

[0068]FIG. 42 shows the amino acid sequence (SEQ ID NO:42) derived fromthe coding sequence of SEQ ID NO:41 shown in FIG. 41.

[0069]FIG. 43 shows a nucleotide sequence (SEQ ID NO:43) of a nativesequence PRO6016 cDNA, wherein SEQ ID NO:43 is a clone designated hereinas “DNA96881-2699”.

[0070]FIG. 44 shows the amino acid sequence (SEQ ID NO:44) derived fromthe coding sequence of SEQ ID NO:43 shown in FIG. 43.

[0071]FIG. 45 shows a nucleotide sequence (SEQ ID NO:45) of a nativesequence PRO4499 cDNA, wherein SEQ ID NO:45 is a clone designated hereinas “DNA96889-2641”.

[0072]FIG. 46 shows the amino acid sequence (SEQ ID NO:46) derived fromthe coding sequence of SEQ ID NO:45 shown in FIG. 45.

[0073]FIG. 47 shows a nucleotide sequence (SEQ ID NO:47) of a nativesequence PRO4487 cDNA, wherein SEQ ID NO:47 is a clone designated hereinas “DNA96898-2640”.

[0074]FIG. 48 shows the amino acid sequence (SEQ ID NO:48) derived fromthe coding sequence of SEQ ID NO:47 shown in FIG. 47.

[0075]FIG. 49 shows a nucleotide sequence (SEQ ID NO:49) of a nativesequence PRO4980 cDNA, wherein SEQ ID NO:49 is a clone designated hereinas “DNA97003-2649”.

[0076]FIG. 50 shows the amino acid sequence (SEQ ID NO:50) derived fromthe coding sequence of SEQ ID NO:49 shown in FIG. 49.

[0077]FIG. 51 shows a nucleotide sequence (SEQ ID NO:51) of a nativesequence PRO6018 cDNA, wherein SEQ ID NO:51 is a clone designated hereinas “DNA98565-2701”.

[0078]FIG. 52 shows the amino acid sequence (SEQ ID NO:52) derived fromthe coding sequence of SEQ ID NO:51 shown in FIG. 51.

[0079]FIG. 53 shows a nucleotide sequence (SEQ ID NO:53) of a nativesequence PRO7168 cDNA, wherein SEQ ID NO:53 is a clone designated hereinas “DNA102846-2742”.

[0080]FIG. 54 shows the amino acid sequence (SEQ ID NO:54) derived fromthe coding sequence of SEQ ID NO:53 shown in FIG. 53.

[0081]FIG. 55 shows a nucleotide sequence (SEQ ID NO:55) of a nativesequence PRO6308 cDNA, wherein SEQ ID NO:55 is a clone designated hereinas “DNA102847-2726”.

[0082]FIG. 56 shows the amino acid sequence (SEQ ID NO:56) derived fromthe coding sequence of SEQ ID NO:55 shown in FIG. 55.

[0083]FIG. 57 shows a nucleotide sequence (SEQ ID NO:57) of a nativesequence PRO6000 cDNA, wherein SEQ ID NO:57 is a clone designated hereinas “DNA102880-2689”.

[0084]FIG. 58 shows the amino acid sequence (SEQ ID NO:58) derived fromthe coding sequence of SEQ ID NO:57 shown in FIG. 57.

[0085]FIG. 59 shows a nucleotide sequence (SEQ ID NO:59) of a nativesequence PRO6006 cDNA, wherein SEQ ID NO:59 is a clone designated hereinas “DNA105782-2693”.

[0086]FIG. 60 shows the amino acid sequence (SEQ ID NO:60) derived fromthe coding sequence of SEQ ID NO:59 shown in FIG. 59.

[0087]FIG. 61 shows a nucleotide sequence (SEQ ID NO:61) of a nativesequence PRO5800 cDNA, wherein SEQ ID NO:61 is a clone designated hereinas “DNA108912-2680”.

[0088]FIG. 62 shows the amino acid sequence (SEQ ID NO:62) derived fromthe coding sequence of SEQ ID NO:61 shown in FIG. 61.

[0089]FIG. 63 shows a nucleotide sequence (SEQ ID NO:63) of a nativesequence PRO7476 cDNA, wherein SEQ ID NO:63 is a clone designated hereinas “DNA1 15253-2757”.

[0090]FIG. 64 shows the amino acid sequence (SEQ ID NO:64) derived fromthe coding sequence of SEQ ID NO:63 shown in FIG. 63.

[0091]FIG. 65 shows a nucleotide sequence (SEQ ID NO:65) of a nativesequence PRO6496 cDNA, wherein SEQ ID NO:65 is a clone designated hereinas “DNA119302-2737”.

[0092]FIG. 66 shows the amino acid sequence (SEQ ID NO:66) derived fromthe coding sequence of SEQ ID NO:65 shown in FIG. 65.

[0093]FIG. 67 shows a nucleotide sequence (SEQ ID NO:67) of a nativesequence PRO7422 cDNA, wherein SEQ ID NO:67 is a clone designated hereinas “DNA1 19536-2752”.

[0094]FIG. 68 shows the amino acid sequence (SEQ ID NO:68) derived fromthe coding sequence of SEQ ID NO:67 shown in FIG. 67.

[0095]FIG. 69 shows a nucleotide sequence (SEQ ID NO:69) of a nativesequence PRO7431cDNA, wherein SEQ ID NO:69 is a clone designated hereinas “DNA119542-2754”.

[0096]FIG. 70 shows the amino acid sequence (SEQ ID NO:70) derived fromthe coding sequence of SEQ ID NO:69 shown in FIG. 69.

[0097]FIG. 71 shows a nucleotide sequence (SEQ ID NO:71) of a nativesequence PRO10275 cDNA, wherein SEQ ID NO:71 is a clone designatedherein as “DNA143498-2824”.

[0098]FIG. 72 shows the amino acid sequence (SEQ ID NO:72) derived fromthe coding sequence of SEQ ID NO:71 shown in FIG. 71.

[0099]FIG. 73 shows a nucleotide sequence (SEQ ID NO:73) of a nativesequence PRO10268 cDNA, wherein SEQ ID NO:73 is a clone designatedherein as “DNA145583-2820”.

[0100]FIG. 74 shows the amino acid sequence (SEQ ID NO:74) derived fromthe coding sequence of SEQ ID NO:73 shown in FIG. 73.

[0101]FIG. 75 shows a nucleotide sequence (SEQ ID NO:75) of a nativesequence PRO20080 cDNA, wherein SEQ ID NO:75 is a clone designatedherein as “DNA161000-2896”.

[0102]FIG. 76 shows the amino acid sequence (SEQ ID NO:76) derived fromthe coding sequence of SEQ ID NO:75 shown in FIG. 75.

[0103]FIG. 77 shows a nucleotide sequence (SEQ ID NO:77) of a nativesequence PRO21207 cDNA, wherein SEQ ID NO:77 is a clone designatedherein as “DNA161005-2943”.

[0104]FIG. 78 shows the amino acid sequence (SEQ ID NO:78) derived fromthe coding sequence of SEQ ID NO:77 shown in FIG. 77.

[0105]FIG. 79 shows a nucleotide sequence (SEQ ID NO:79) of a nativesequence PRO28633 cDNA, wherein SEQ ID NO:79 is a clone designatedherein as “DNA170245-3053”.

[0106]FIG. 80 shows the amino acid sequence (SEQ ID NO:80) derived fromthe coding sequence of SEQ ID NO:79 shown in FIG. 79.

[0107]FIG. 81 shows a nucleotide sequence (SEQ ID NO:81) of a nativesequence PRO20933 cDNA, wherein SEQ ID NO:81 is a clone designatedherein as “DNA171771-2919”.

[0108]FIG. 82 shows the amino acid sequence (SEQ ID NO:82) derived fromthe coding sequence of SEQ ID NO:81 shown in FIG. 81.

[0109]FIG. 83 shows a nucleotide sequence (SEQ ID NO:83) of a nativesequence PRO21383 cDNA, wherein SEQ ID NO:83 is a clone designatedherein as “DNA173157-2981”.

[0110]FIG. 84 shows the amino acid sequence (SEQ ID NO:84) derived fromthe coding sequence of SEQ ID NO:83 shown in FIG. 83.

[0111]FIG. 85 shows a nucleotide sequence (SEQ ID NO:85) of a nativesequence PRO21485 cDNA, wherein SEQ ID NO:85 is a clone designatedherein as “DNA175734-2985”.

[0112]FIG. 86 shows the amino acid sequence (SEQ ID NO:86) derived fromthe coding sequence of SEQ ID NO:85 shown in FIG. 85.

[0113]FIG. 87 shows a nucleotide sequence (SEQ ID NO:87) of a nativesequence PRO28700 cDNA, wherein SEQ ID NO:87 is a clone designatedherein as “DNA176108-3040”.

[0114]FIG. 88 shows the amino acid sequence (SEQ ID NO:88) derived fromthe coding sequence of SEQ ID NO:87 shown in FIG. 87.

[0115]FIG. 89 shows a nucleotide sequence (SEQ ID NO:89) of a nativesequence PRO34012 cDNA, wherein SEQ ID NO:89 is a clone designatedherein as “DNA190710-3028”.

[0116]FIG. 90 shows the amino acid sequence (SEQ ID NO:90) derived fromthe coding sequence of SEQ ID NO:89 shown in FIG. 89.

[0117]FIG. 91 shows a nucleotide sequence (SEQ ID NO:91) of a nativesequence PRO34003 cDNA, wherein SEQ ID NO:91 is a clone designatedherein as “DNA190803-3019”.

[0118]FIG. 92 shows the amino acid sequence (SEQ ID NO:92) derived fromthe coding sequence of SEQ ID NO:91 shown in FIG. 91.

[0119]FIG. 93 shows a nucleotide sequence (SEQ ID NO:93) of a nativesequence PRO34274 cDNA, wherein SEQ ID NO:93 is a clone designatedherein as “DNA191064-3069”.

[0120]FIG. 94 shows the amino acid sequence (SEQ ID NO:94) derived fromthe coding sequence of SEQ ID NO:93 shown in FIG. 93.

[0121] FIGS. 95A-95B shows a nucleotide sequence (SEQ ID NO:95) of anative sequence PRO34001 cDNA, wherein SEQ ID NO:95 is a clonedesignated herein as “DNA194909-3013”.

[0122]FIG. 96 shows the amino acid sequence (SEQ ID NO:96) derived fromthe coding sequence of SEQ ID NO:95 shown in FIGS. 95A-95B.

[0123]FIG. 97 shows a nucleotide sequence (SEQ ID NO:97) of a nativesequence PRO34009 cDNA, wherein SEQ ID NO:97 is a clone designatedherein as “DNA203532-3029”.

[0124]FIG. 98 shows the amino acid sequence (SEQ ID NO:98) derived fromthe coding sequence of SEQ ID NO:97 shown in FIG. 97.

[0125]FIG. 99 shows a nucleotide sequence (SEQ ID NO:99) of a nativesequence PRO34192 cDNA, wherein SEQ ID NO:99 is a clone designatedherein as “DNA213858-3060”.

[0126]FIG. 100 shows the amino acid sequence (SEQ ID NO:100) derivedfrom the coding sequence of SEQ ID NO:99 shown in FIG. 99.

[0127]FIG. 101 shows a nucleotide sequence (SEQ ID NO:101) of a nativesequence PRO34564 cDNA, wherein SEQ ID NO:101 is a clone designatedherein as “DNA216676-3083”.

[0128]FIG. 102 shows the amino acid sequence (SEQ ID NO:102) derivedfrom the coding sequence of SEQ ID NO:101 shown in FIG. 101.

[0129]FIG. 103 shows a nucleotide sequence (SEQ ID NO:103) of a nativesequence PRO35444 cDNA, wherein SEQ ID NO:103 is a clone designatedherein as “DNA222653-3104”.

[0130]FIG. 104 shows the amino acid sequence (SEQ ID NO:104) derivedfrom the coding sequence of SEQ ID NO:103 shown in FIG. 103.

[0131]FIG. 105 shows a nucleotide sequence (SEQ ID NO:105) of a nativesequence PRO5998 cDNA, wherein SEQ ID NO:105 is a clone designatedherein as “DNA96897-2688”.

[0132]FIG. 106 shows the amino acid sequence (SEQ ID NO:106) derivedfrom the coding sequence of SEQ ID NO:105 shown in FIG. 105.

[0133]FIG. 107 shows a nucleotide sequence (SEQ ID NO:107) of a nativesequence PRO19651 cDNA, wherein SEQ ID NO:107 is a clone designatedherein as “DNA142917-3081”.

[0134]FIG. 108 shows the amino acid sequence (SEQ ID NO:108) derivedfrom the coding sequence of SEQ ID NO:107 shown in FIG. 107.

[0135]FIG. 109 shows a nucleotide sequence (SEQ ID NO:109) of a nativesequence PRO20221 cDNA, wherein SEQ ID NO:109 is a clone designatedherein as “DNA142930-2914”.

[0136]FIG. 110 shows the amino acid sequence (SEQ ID NO:110) derivedfrom the coding sequence of SEQ ID NO:109 shown in FIG. 109.

[0137]FIG. 111 shows a nucleotide sequence (SEQ ID NO:111) of a nativesequence PRO21434 cDNA, wherein SEQ ID NO:111 is a clone designatedherein as “DNA 147253-2983”.

[0138]FIG. 112 shows the amino acid sequence (SEQ ID NO:112) derivedfrom the coding sequence of SEQ ID NO:111 shown in FIG. 111.

[0139]FIG. 113 shows a nucleotide sequence (SEQ ID NO:113) of a nativesequence PRO19822 cDNA, wherein SEQ ID NO:113 is a clone designatedherein as “DNA149927-2887”.

[0140]FIG. 114 shows the amino acid sequence (SEQ ID NO:114) derivedfrom the coding sequence of SEQ ID NO:113 shown in FIG. 113.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0141] I. Definitions

[0142] The terms “PRO polypeptide” and “PRO” as used herein and whenimmediately followed by a numerical designation refer to variouspolypeptides, wherein the complete designation (i.e., PRO/number) refersto specific polypeptide sequences as described herein. The terms“PRO/number polypeptide” and “PRO/number” wherein the term “number” isprovided as an actual numerical designation as used herein encompassnative sequence polypeptides and polypeptide variants (which are furtherdefined herein). The PRO polypeptides described herein may be isolatedfrom a variety of sources, such as from human tissue types or fromanother source, or prepared by recombinant or synthetic methods. Theterm “PRO polypeptide” refers to each individual PRO/number polypeptidedisclosed herein. All disclosures in this specification which refer tothe “PRO polypeptide” refer to each of the polypeptides individually aswell as jointly. For example, descriptions of the preparation of,purification of, derivation of, formation of antibodies to or against,administration of, compositions containing, treatment of a disease with,etc., pertain to each polypeptide of the invention individually. Theterm “PRO polypeptide” also includes variants of the PRO/numberpolypeptides disclosed herein.

[0143] A “native sequence PRO polypeptide” comprises a polypeptidehaving the same amino acid sequence as the corresponding PRO polypeptidederived from nature. Such native sequence PRO polypeptides can beisolated from nature or can be produced by recombinant or syntheticmeans. The term “native sequence PRO polypeptide” specificallyencompasses naturally-occurring truncated or secreted forms of thespecific PRO polypeptide (e.g., an extracellular domain sequence),naturally-occurring variant forms (e.g., alternatively spliced forms)and naturally-occurring allelic variants of the polypeptide. In variousembodiments of the invention, the native sequence PRO polypeptidesdisclosed herein are mature or full-length native sequence polypeptidescomprising the full-length amino acids sequences shown in theaccompanying figures. Start and stop codons are shown in bold font andunderlined in the figures. However, while the PRO polypeptide disclosedin the accompanying figures are shown to begin with methionine residuesdesignated herein as amino acid position 1 in the figures, it isconceivable and possible that other methionine residues located eitherupstream or downstream from the amino acid position 1 in the figures maybe employed as the starting amino acid residue for the PRO polypeptides.

[0144] The PRO polypeptide “extracellular domain” or “ECD” refers to aform of the PRO polypeptide which is essentially free of thetransmembrane and cytoplasmic domains. Ordinarily, a PRO polypeptide ECDwill have less than 1% of such transmembrane and/or cytoplasmic domainsand preferably, will have less than 0.5% of such domains. It will beunderstood that any transmembrane domains identified for the PROpolypeptides of the present invention are identified pursuant tocriteria routinely employed in the art for identifying that type ofhydrophobic domain. The exact boundaries of a transmembrane domain mayvary but most likely by no more than about 5 amino acids at either endof the domain as initially identified herein. Optionally, therefore, anextracellular domain of a PRO polypeptide may contain from about 5 orfewer amino acids on either side of the transmembranedomain/extracellular domain boundary as identified in the Examples orspecification and such polypeptides, with or without the associatedsignal peptide, and nucleic acid encoding them, are comtemplated by thepresent invention.

[0145] The approximate location of the “signal peptides” of the variousPRO polypeptides disclosed herein are shown in the present specificationand/or the accompanying figures. It is noted, however, that theC-terminal boundary of a signal peptide may vary, but most likely by nomore than about 5 amino acids on either side of the signal peptideC-terminal boundary as initially identified herein, wherein theC-terminal boundary of the signal peptide may be identified pursuant tocriteria routinely employed in the art for identifying that type ofamino acid sequence element (e.g., Nielsen et al., Prot. Eng. 10:1-6(1997) and von Heinje et al., Nucl. Acids. Res. 14:4683-4690 (1986)).Moreover, it is also recognized that, in some cases, cleavage of asignal sequence from a secreted polypeptide is not entirely uniform,resulting in more than one secreted species. These mature polypeptides,where the signal peptide is cleaved within no more than about 5 aminoacids on either side of the C-terminal boundary of the signal peptide asidentified herein, and the polynucleotides encoding them, arecontemplated by the present invention.

[0146] “PRO polypeptide variant” means an active PRO polypeptide asdefined above or below having at least about 80% amino acid sequenceidentity with a full-length native sequence PRO polypeptide sequence asdisclosed herein, a PRO polypeptide sequence lacking the signal peptideas disclosed herein, an extracellular domain of a PRO polypeptide, withor without the signal peptide, as disclosed herein or any other fragmentof a full-length PRO polypeptide sequence as disclosed herein. Such PROpolypeptide variants include, for instance, PRO polypeptides wherein oneor more amino acid residues are added, or deleted, at the N- orC-terminus of the full-length native amino acid sequence. Ordinarily, aPRO polypeptide variant will have at least about 80% amino acid sequenceidentity, alternatively at least about 81% amino acid sequence identity,alternatively at least about 82% amino acid sequence identity,alternatively at least about 83% amino acid sequence identity,alternatively at least about 84% amino acid sequence identity,alternatively at least about 85% amino acid sequence identity,alternatively at least about 86% amino acid sequence identity,alternatively at least about 87% amino acid sequence identity,alternatively at least about 88% amino acid sequence identity,alternatively at least about 89% amino acid sequence identity,alternatively at least about 90% amino acid sequence identity,alternatively at least about 91% amino acid sequence identity,alternatively at least about 92% amino acid sequence identity,alternatively at least about 93% amino acid sequence identity,alternatively at least about 94% amino acid sequence identity,alternatively at least about 95% amino acid sequence identity,alternatively at least about 96% amino acid sequence identity,alternatively at least about 97% amino acid sequence identity,alternatively at least about 98% amino acid sequence identity andalternatively at least about 99% amino acid sequence identity to afull-length native sequence PRO polypeptide sequence as disclosedherein, a PRO polypeptide sequence lacking the signal peptide asdisclosed herein, an extracellular domain of a PRO polypeptide, with orwithout the signal peptide, as disclosed herein or any otherspecifically defined fragment of a full-length PRO polypeptide sequenceas disclosed herein. Ordinarily, PRO variant polypeptides are at leastabout 10 amino acids in length, alternatively at least about 20 aminoacids in length, alternatively at least about 30 amino acids in length,alternatively at least about 40 amino acids in length, alternatively atleast about 50 amino acids in length, alternatively at least about 60amino acids in length, alternatively at least about 70 amino acids inlength, alternatively at least about 80 amino acids in length,alternatively at least about 90 amino acids in length, alternatively atleast about 100 amino acids in length, alternatively at least about 150amino acids in length, alternatively at least about 200 amino acids inlength, alternatively at least about 300 amino acids in length, or more.

[0147] “Percent (%) amino acid sequence identity” with respect to thePRO polypeptide sequences identified herein is defined as the percentageof amino acid residues in a candidate sequence that are identical withthe amino acid residues in the specific PRO polypeptide sequence, afteraligning the sequences and introducing gaps, if necessary, to achievethe maximum percent sequence identity, and not considering anyconservative substitutions as part of the sequence identity. Alignmentfor purposes of determining percent amino acid sequence identity can beachieved in various ways that are within the skill in the art, forinstance, using publicly available computer software such as BLAST,BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the artcan determine appropriate parameters for measuring alignment, includingany algorithms needed to achieve maximal alignment over the full lengthof the sequences being compared. For purposes herein, however, % aminoacid sequence identity values are generated using the sequencecomparison computer program ALIGN-2, wherein the complete source codefor the ALIGN-2 program is provided in Table 1 below. The ALIGN-2sequence comparison computer program was authored by Genentech, Inc. andthe source code shown in Table 1 below has been filed with userdocumentation in the U.S. Copyright Office, Washington D.C., 20559,where it is registered under U.S. Copyright Registration No. TXU510087.The ALIGN-2 program is publicly available through Genentech, Inc., SouthSan Francisco, Calif. or may be compiled from the source code providedin Table 1 below. The ALIGN-2 program should be compiled for use on aUNIX operating system, preferably digital UNIX V4.0D. All sequencecomparison parameters are set by the ALIGN-2 program and do not vary.

[0148] In situations where ALIGN-2 is employed for amino acid sequencecomparisons, the % amino acid sequence identity of a given amino acidsequence A to, with, or against a given amino acid sequence B (which canalternatively be phrased as a given amino acid sequence A that has orcomprises a certain % amino acid sequence identity to, with, or againsta given amino acid sequence B) is calculated as follows:

100 times the fraction X/Y

[0149] where X is the number of amino acid residues scored as identicalmatches by the sequence alignment program ALIGN-2 in that program'salignment of A and B, and where Y is the total number of amino acidresidues in B. It will be appreciated that where the length of aminoacid sequence A is not equal to the length of amino acid sequence B, the% amino acid sequence identity of A to B will not equal the % amino acidsequence identity of B to A. As examples of % amino acid sequenceidentity calculations using this method, Tables 2 and 3 demonstrate howto calculate the % amino acid sequence identity of the amino acidsequence designated “Comparison Protein” to the amino acid sequencedesignated “PRO”, wherein “PRO” represents the amino acid sequence of ahypothetical PRO polypeptide of interest, “Comparison Protein”represents the amino acid sequence of a polypeptide against which the“PRO” polypeptide of interest is being compared, and “X, “Y” and “Z”each represent different hypothetical amino acid residues.

[0150] Unless specifically stated otherwise, all % amino acid sequenceidentity values used herein are obtained as described in the immediatelypreceding paragraph using the ALIGN-2 computer program. However, % aminoacid sequence identity values may also be obtained as described below byusing the WU-BLAST-2 computer program (Altschul et al., Methods inEnzymology 266:460-480 (1996)). Most of the WU-BLAST-2 search parametersare set to the default values. Those not set to default values, i.e.,the adjustable parameters, are set with the following values: overlapspan=1, overlap fraction=0.125, word threshold (T)=11, and scoringmatrix=BLOSUM62. When WU-BLAST-2 is employed, a % amino acid sequenceidentity value is determined by dividing (a) the number of matchingidentical amino acid residues between the amino acid sequence of the PROpolypeptide of interest having a sequence derived from the native PROpolypeptide and the comparison amino acid sequence of interest (i.e.,the sequence against which the PRO polypeptide of interest is beingcompared which may be a PRO variant polypeptide) as determined byWU-BLAST-2 by (b) the total number of amino acid residues of the PROpolypeptide of interest. For example, in the statement “a polypeptidecomprising an the amino acid sequence A which has or having at least 80%amino acid sequence identity to the amino acid sequence B”, the aminoacid sequence A is the comparison amino acid sequence of interest andthe amino acid sequence B is the amino acid sequence of the PROpolypeptide of interest.

[0151] Percent amino acid sequence identity may also be determined usingthe sequence comparison program NCBI-BLAST2 (Altschul et al., NucleicAcids Res. 25:3389-3402 (1997)). The NCBI-BLAST2 sequence comparisonprogram may be downloaded from http://www.ncbi.nlm.nih.gov or otherwiseobtained from the National Institute of Health, Bethesda, Md.NCBI-BLAST2 uses several search parameters, wherein all of those searchparameters are set to default values including, for example, unmask=yes,strand=all, expected occurrences=10, minimum low complexity length=15/5,multi-pass e-value=0.01, constant for multi-pass=25, dropoff for finalgapped alignment=25 and scoring matrix=BLOSUM62.

[0152] In situations where NCBI-BLAST2 is employed for amino acidsequence comparisons, the % amino acid sequence identity of a givenamino acid sequence A to, with, or against a given amino acid sequence B(which can alternatively be phrased as a given amino acid sequence Athat has or comprises a certain % amino acid sequence identity to, with,or against a given amino acid sequence B) is calculated as follows:

100 times the fraction X/Y

[0153] where X is the number of amino acid residues scored as identicalmatches by the sequence alignment program NCBI-BLAST2 in that program'salignment of A and B, and where Y is the total number of amino acidresidues in B. It will be appreciated that where the length of aminoacid sequence A is not equal to the length of amino acid sequence B, the% amino acid sequence identity of A to B will not equal the % amino acidsequence identity of B to A.

[0154] “PRO variant polynucleotide” or “PRO variant nucleic acidsequence” means a nucleic acid molecule which encodes an active PROpolypeptide as defined below and which has at least about 80% nucleicacid sequence identity with a nucleotide acid sequence encoding afull-length native sequence PRO polypeptide sequence as disclosedherein, a full-length native sequence PRO polypeptide sequence lackingthe signal peptide as disclosed herein, an extracellular domain of a PROpolypeptide, with or without the signal peptide, as disclosed herein orany other fragment of a full-length PRO polypeptide sequence asdisclosed herein. Ordinarily, a PRO variant polynucleotide will have atleast about 80% nucleic acid sequence identity, alternatively at leastabout 81% nucleic acid sequence identity, alternatively at least about82% nucleic acid sequence identity, alternatively at least about 83%nucleic acid sequence identity, alternatively at least about 84% nucleicacid sequence identity, alternatively at least about 85% nucleic acidsequence identity, alternatively at least about 86% nucleic acidsequence identity, alternatively at least about 87% nucleic acidsequence identity, alternatively at least about 88% nucleic acidsequence identity, alternatively at least about 89% nucleic acidsequence identity, alternatively at least about 90% nucleic acidsequence identity, alternatively at least about 91% nucleic acidsequence identity, alternatively at least about 92% nucleic acidsequence identity, alternatively at least about 93% nucleic acidsequence identity, alternatively at least about 94% nucleic acidsequence identity, alternatively at least about 95% nucleic acidsequence identity, alternatively at least about 96% nucleic acidsequence identity, alternatively at least about 97% nucleic acidsequence identity, alternatively at least about 98% nucleic acidsequence identity and alternatively at least about 99% nucleic acidsequence identity with a nucleic acid sequence encoding a full-lengthnative sequence PRO polypeptide sequence as disclosed herein, afull-length native sequence PRO polypeptide sequence lacking the signalpeptide as disclosed herein, an extracellular domain of a PROpolypeptide, with or without the signal sequence, as disclosed herein orany other fragment of a full-length PRO polypeptide sequence asdisclosed herein. Variants do not encompass the native nucleotidesequence.

[0155] Ordinarily, PRO variant polynucleotides are at least about 30nucleotides in length, alternatively at least about 60 nucleotides inlength, alternatively at least about 90 nucleotides in length,alternatively at least about 120 nucleotides in length, alternatively atleast about 150 nucleotides in length, alternatively at least about 180nucleotides in length, alternatively at least about 210 nucleotides inlength, alternatively at least about 240 nucleotides in length,alternatively at least about 270 nucleotides in length, alternatively atleast about 300 nucleotides in length, alternatively at least about 450nucleotides in length, alternatively at least about 600 nucleotides inlength, alternatively at least about 900 nucleotides in length, or more.

[0156] “Percent (%) nucleic acid sequence identity” with respect toPRO-encoding nucleic acid sequences identified herein is defined as thepercentage of nucleotides in a candidate sequence that are identicalwith the nucleotides in the PRO nucleic acid sequence of interest, afteraligning the sequences and introducing gaps, if necessary, to achievethe maximum percent sequence identity. Alignment for purposes ofdetermining percent nucleic acid sequence identity can be achieved invarious ways that are within the skill in the art, for instance, usingpublicly available computer software such as BLAST, BLAST-2, ALIGN orMegalign (DNASTAR) software. For purposes herein, however, % nucleicacid sequence identity values are generated using the sequencecomparison computer program ALIGN-2, wherein the complete source codefor the ALIGN-2 program is provided in Table 1 below. The ALIGN-2sequence comparison computer program was authored by Genentech, Inc. andthe source code shown in Table 1 below has been filed with userdocumentation in the U.S. Copyright Office, Washington D.C., 20559,where it is registered under U.S. Copyright Registration No. TXU510087.The ALIGN-2 program is publicly available through Genentech, Inc., SouthSan Francisco, Calif. or may be compiled from the source code providedin Table 1 below. The ALIGN-2 program should be compiled for use on aUNIX operating system, preferably digital UNIX V4.0D. All sequencecomparison parameters are set by the ALIGN-2 program and do not vary.

[0157] In situations where ALIGN-2 is employed for nucleic acid sequencecomparisons, the % nucleic acid sequence identity of a given nucleicacid sequence C to, with, or against a given nucleic acid sequence D(which can alternatively be phrased as a given nucleic acid sequence Cthat has or comprises a certain % nucleic acid sequence identity to,with, or against a given nucleic acid sequence D) is calculated asfollows:

100 times the fraction W/Z

[0158] where W is the number of nucleotides scored as identical matchesby the sequence alignment program ALIGN-2 in that program's alignment ofC and D, and where Z is the total number of nucleotides in D. It will beappreciated that where the length of nucleic acid sequence C is notequal to the length of nucleic acid sequence D, the % nucleic acidsequence identity of C to D will not equal the % nucleic acid sequenceidentity of D to C. As examples of % nucleic acid sequence identitycalculations, Tables 4 and 5, demonstrate how to calculate the % nucleicacid sequence identity of the nucleic acid sequence designated“Comparison DNA” to the nucleic acid sequence designated “PRO-DNA”,wherein “PRO-DNA” represents a hypothetical PRO-encoding nucleic acidsequence of interest, “Comparison DNA” represents the nucleotidesequence of a nucleic acid molecule against which the “PRO-DNA” nucleicacid molecule of interest is being compared, and “N”, “L” and “V” eachrepresent different hypothetical nucleotides.

[0159] Unless specifically stated otherwise, all % nucleic acid sequenceidentity values used herein are obtained as described in the immediatelypreceding paragraph using the ALIGN-2 computer program. However, %nucleic acid sequence identity values may also be obtained as describedbelow by using the WU-BLAST-2 computer program (Altschul et al., Methodsin Enzymology 266:460-480 (1996)). Most of the WU-BLAST-2 searchparameters are set to the default values. Those not set to defaultvalues, i.e., the adjustable parameters, are set with the followingvalues: overlap span=1, overlap fraction=0.125, word threshold (T)=11,and scoring matrix=BLOSUM62. When WU-BLAST-2 is employed, a % nucleicacid sequence identity value is determined by dividing (a) the number ofmatching identical nucleotides between the nucleic acid sequence of thePRO polypeptide-encoding nucleic acid molecule of interest having asequence derived from the native sequence PRO polypeptide-encodingnucleic acid and the comparison nucleic acid molecule of interest (i.e.,the sequence against which the PRO polypeptide-encoding nucleic acidmolecule of interest is being compared which may be a variant PROpolynucleotide) as determined by WU-BLAST-2 by (b) the total number ofnucleotides of the PRO polypeptide-encoding nucleic acid molecule ofinterest. For example, in the statement “an isolated nucleic acidmolecule comprising a nucleic acid sequence A which has or having atleast 80% nucleic acid sequence identity to the nucleic acid sequenceB”, the nucleic acid sequence A is the comparison nucleic acid moleculeof interest and the nucleic acid sequence B is the nucleic acid sequenceof the PRO polypeptide-encoding nucleic acid molecule of interest.

[0160] Percent nucleic acid sequence identity may also be determinedusing the sequence comparison program NCBI-BLAST2 (Altschul et al.,Nucleic Acids Res. 25:3389-3402 (1997)). The NCBI-BLAST2 sequencecomparison program may be downloaded from http://www.ncbi.nlm.nih.gov orotherwise obtained from the National Institute of Health, Bethesda, Md.NCBI-BLAST2 uses several search parameters, wherein all of those searchparameters are set to default values including, for example, unmask=yes,strand=all, expected occurrences=10, minimum low complexity length=15/5,multi-pass e-value=0.01, constant for multi-pass=25, dropoff for finalgapped alignment=25 and scoring matrix=BLOSUM62.

[0161] In situations where NCBI-BLAST2 is employed for sequencecomparisons, the % nucleic acid sequence identity of a given nucleicacid sequence C to, with, or against a given nucleic acid sequence D(which can alternatively be phrased as a given nucleic acid sequence Cthat has or comprises a certain % nucleic acid sequence identity to,with, or against a given nucleic acid sequence D) is calculated asfollows:

100 times the fraction W/Z

[0162] where W is the number of nucleotides scored as identical matchesby the sequence alignment program NCBI-BLAST2 in that program'salignment of C and D, and where Z is the total number of nucleotides inD. It will be appreciated that where the length of nucleic acid sequenceC is not equal to the length of nucleic acid sequence D, the % nucleicacid sequence identity of C to D will not equal the % nucleic acidsequence identity of D to C.

[0163] In other embodiments, PRO variant polynucleotides are nucleicacid molecules that encode an active PRO polypeptide and which arecapable of hybridizing, preferably under stringent hybridization andwash conditions, to nucleotide sequences encoding a full-length PROpolypeptide as disclosed herein. PRO variant polypeptides may be thosethat are encoded by a PRO variant polynucleotide.

[0164] “Isolated,” when used to describe the various polypeptidesdisclosed herein, means polypeptide that has been identified andseparated and/or recovered from a component of its natural environment.Contaminant components of its natural environment are materials thatwould typically interfere with diagnostic or therapeutic uses for thepolypeptide, and may include enzymes, hormones, and other proteinaceousor non-proteinaceous solutes. In preferred embodiments, the polypeptidewill be purified (1) to a degree sufficient to obtain at least 15residues of N-terminal or internal amino acid sequence by use of aspinning cup sequenator, or (2) to homogeneity by SDS-PAGE undernon-reducing or reducing conditions using Coomassie blue or, preferably,silver stain. Isolated polypeptide includes polypeptide in situ withinrecombinant cells, since at least one component of the PRO polypeptidenatural environment will not be present. Ordinarily, however, isolatedpolypeptide will be prepared by at least one purification step.

[0165] An “isolated” PRO polypeptide-encoding nucleic acid or otherpolypeptide-encoding nucleic acid is a nucleic acid molecule that isidentified and separated from at least one contaminant nucleic acidmolecule with which it is ordinarily associated in the natural source ofthe polypeptide-encoding nucleic acid. An isolated polypeptide-encodingnucleic acid molecule is other than in the form or setting in which itis found in nature. Isolated polypeptide-encoding nucleic acid moleculestherefore are distinguished from the specific polypeptide-encodingnucleic acid molecule as it exists in natural cells. However, anisolated polypeptide-encoding nucleic acid molecule includespolypeptide-encoding nucleic acid molecules contained in cells thatordinarily express the polypeptide where, for example, the nucleic acidmolecule is in a chromosomal location different from that of naturalcells.

[0166] The term “control sequences” refers to DNA sequences necessaryfor the expression of an operably linked coding sequence in a particularhost organism. The control sequences that are suitable for prokaryotes,for example, include a promoter, optionally an operator sequence, and aribosome binding site. Eukaryotic cells are known to utilize promoters,polyadenylation signals, and enhancers.

[0167] Nucleic acid is “operably linked” when it is placed into afunctional relationship with another nucleic acid sequence. For example,DNA for a presequence or secretory leader is operably linked to DNA fora polypeptide if it is expressed as a preprotein that participates inthe secretion of the polypeptide; a promoter or enhancer is operablylinked to a coding sequence if it affects the transcription of thesequence; or a ribosome binding site is operably linked to a codingsequence if it is positioned so as to facilitate translation. Generally,“operably linked” means that the DNA sequences being linked arecontiguous, and, in the case of a secretory leader, contiguous and inreading phase. However, enhancers do not have to be contiguous. Linkingis accomplished by ligation at convenient restriction sites. If suchsites do not exist, the synthetic oligonucleotide adaptors or linkersare used in accordance with conventional practice.

[0168] The term “antibody” is used in the broadest sense andspecifically covers, for example, single anti-PRO monoclonal antibodies(including agonist, antagonist, and neutralizing antibodies), anti-PROantibody compositions with polyepitopic specificity, single chainanti-PRO antibodies, and fragments of anti-PRO antibodies (see below).The term “monoclonal antibody” as used herein refers to an antibodyobtained from a population of substantially homogeneous antibodies,i.e., the individual antibodies comprising the population are identicalexcept for possible naturally-occurring mutations that may be present inminor amounts.

[0169] “Stringency” of hybridization reactions is readily determinableby one of ordinary skill in the art, and generally is an empiricalcalculation dependent upon probe length, washing temperature, and saltconcentration. In general, longer probes require higher temperatures forproper annealing, while shorter probes need lower temperatures.Hybridization generally depends on the ability of denatured DNA toreanneal when complementary strands are present in an environment belowtheir melting temperature. The higher the degree of desired homologybetween the probe and hybridizable sequence, the higher the relativetemperature which can be used. As a result, it follows that higherrelative temperatures would tend to make the reaction conditions morestringent, while lower temperatures less so. For additional details andexplanation of stringency of hybridization reactions, see Ausubel etal., Current Protocols in Molecular Biology, Wiley IntersciencePublishers, (1995).

[0170] “Stringent conditions” or “high stringency conditions”, asdefined herein, may be identified by those that: (1) employ low ionicstrength and high temperature for washing, for example 0.015 M sodiumchloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50° C.;(2) employ during hybridization a denaturing agent, such as formamide,for example, 50% (v/v) formamide with 0.1% bovine serum albumin/0.1%Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5with 750 mM sodium chloride, 75 mM sodium citrate at 42° C.; or (3)employ 50% formamide, 5×SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mMsodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5×Denhardt'ssolution, sonicated salmon sperm DNA (50 μg/ml), 0.1% SDS, and 10%dextran sulfate at 42° C., with washes at 42° C. in 0.2×SSC (sodiumchloride citrate) and 50% formamide at 55° C., followed by ahigh-stringency wash consisting of 0.1×SSC containing EDTA at 55° C.

[0171] “Moderately stringent conditions” may be identified as describedby Sambrook et al., Molecular Cloning: A Laboratory Manual, New York:Cold Spring Harbor Press, 1989, and include the use of washing solutionand hybridization conditions (e.g., temperature, ionic strength and%SDS) less stringent that those described above. An example ofmoderately stringent conditions is overnight incubation at 37° C. in asolution comprising: 20% formamide, 5×SSC (150 mM NaCl, 15 mM trisodiumcitrate), 50 mM sodium phosphate (pH 7.6), 5×Denhardt's solution, 10%dextran sulfate, and 20 mg/ml denatured sheared salmon sperm DNA,followed by washing the filters in 1×SSC at about 37-50° C. The skilledartisan will recognize how to adjust the temperature, ionic strength,etc. as necessary to accommodate factors such as probe length and thelike.

[0172] The term “epitope tagged” when used herein refers to a chimericpolypeptide comprising a PRO polypeptide fused to a “tag polypeptide”.The tag polypeptide has enough residues to provide an epitope againstwhich an antibody can be made, yet is short enough such that it does notinterfere with activity of the polypeptide to which it is fused. The tagpolypeptide preferably also is fairly unique so that the antibody doesnot substantially cross-react with other epitopes. Suitable tagpolypeptides generally have at least six amino acid residues and usuallybetween about 8 and 50 amino acid residues (preferably, between about 10and 20 amino acid residues).

[0173] As used herein, the term “immunoadhesin” designates antibody-likemolecules which combine the binding specificity of a heterologousprotein (an “adhesin”) with the effector functions of immunoglobulinconstant domains. Structurally, the immunoadhesins comprise a fusion ofan amino acid sequence with the desired binding specificity which isother than the antigen recognition and binding site of an antibody(i.e., is “heterologous”), and an immunoglobulin constant domainsequence. The adhesin part of an immunoadhesin molecule typically is acontiguous amino acid sequence comprising at least the binding site of areceptor or a ligand. The immunoglobulin constant domain sequence in theimmunoadhesin may be obtained from any immunoglobulin, such as IgG-1,IgG-2, IgG-3, or IgG4 subtypes, IgA (including IgA-1 and IgA-2), IgE,IgD or IgM.

[0174] “Active” or “activity” for the purposes herein refers to form(s)of a PRO polypeptide which retain a biological and/or an immunologicalactivity of native or naturally-occurring PRO, wherein “biological”activity refers to a biological function (either inhibitory orstimulatory) caused by a native or naturally-occurring PRO other thanthe ability to induce the production of an antibody against an antigenicepitope possessed by a native or naturally-occurring PRO and an“immunological” activity refers to the ability to induce the productionof an antibody against an antigenic epitope possessed by a native ornaturally-occurring PRO.

[0175] The term “antagonist” is used in the broadest sense, and includesany molecule that partially or fully blocks, inhibits, or neutralizes abiological activity of a native PRO polypeptide disclosed herein. In asimilar manner, the term “agonist” is used in the broadest sense andincludes any molecule that mimics a biological activity of a native PROpolypeptide disclosed herein. Suitable agonist or antagonist moleculesspecifically include agonist or antagonist antibodies or antibodyfragments, fragments or amino acid sequence variants of native PROpolypeptides, peptides, antisense oligonucleotides, small organicmolecules, etc. Methods for identifying agonists or antagonists of a PROpolypeptide may comprise contacting a PRO polypeptide with a candidateagonist or antagonist molecule and measuring a detectable change in oneor more biological activities normally associated with the PROpolypeptide.

[0176] “Treatment” refers to both therapeutic treatment and prophylacticor preventative measures, wherein the object is to prevent or slow down(lessen) the targeted pathologic condition or disorder. Those in need oftreatment include those already with the disorder as well as those proneto have the disorder or those in whom the disorder is to be prevented.

[0177] “Chronic” administration refers to administration of the agent(s)in a continuous mode as opposed to an acute mode, so as to maintain theinitial therapeutic effect (activity) for an extended period of time.“Intermittent” administration is treatment that is not consecutivelydone without interruption, but rather is cyclic in nature.

[0178] “Mammal” for purposes of treatment refers to any animalclassified as a mammal, including humans, domestic and farm animals, andzoo, sports, or pet animals, such as dogs, cats, cattle, horses, sheep,pigs, goats, rabbits, etc. Preferably, the mammal is human.

[0179] Administration “in combination with” one or more furthertherapeutic agents includes simultaneous (concurrent) and consecutiveadministration in any order.

[0180] “Carriers” as used herein include pharmaceutically acceptablecarriers, excipients, or stabilizers which are nontoxic to the cell ormammal being exposed thereto at the dosages and concentrations employed.Often the physiologically acceptable carrier is an aqueous pH bufferedsolution. Examples of physiologically acceptable carriers includebuffers such as phosphate, citrate, and other organic acids;antioxidants including ascorbic acid; low molecular weight (less thanabout 10 residues) polypeptide; proteins, such as serum albumin,gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, arginine or lysine; monosaccharides, disaccharides, andother carbohydrates including glucose, mannose, or dextrins; chelatingagents such as EDTA; sugar alcohols such as mannitol or sorbitol;salt-forming counterions such as sodium; and/or nonionic surfactantssuch as TWEEN™, polyethylene glycol (PEG), and PLURONICS™.

[0181] “Antibody fragments” comprise a portion of an intact antibody,preferably the antigen binding or variable region of the intactantibody. Examples of antibody fragments include Fab, Fab′, F(ab′)₂, andFv fragments; diabodies; linear antibodies (Zapata et al., Protein Eng.8(10): 1057-1062 [1995]); single-chain antibody molecules; andmultispecific antibodies formed from antibody fragments.

[0182] Papain digestion of antibodies produces two identicalantigen-binding fragments, called “Fab” fragments, each with a singleantigen-binding site, and a residual “Fc” fragment, a designationreflecting the ability to crystallize readily. Pepsin treatment yieldsan F(ab′)₂ fragment that has two antigen-combining sites and is stillcapable of cross-linking antigen.

[0183] “Fv” is the minimum antibody fragment which contains a completeantigen-recognition and -binding site. This region consists of a dimerof one heavy- and one light-chain variable domain in tight, non-covalentassociation. It is in this configuration that the three CDRs of eachvariable domain interact to define an antigen-binding site on thesurface of the V_(H)-V_(L) dimer. Collectively, the six CDRs conferantigen-binding specificity to the antibody. However, even a singlevariable domain (or half of an Fv comprising only three CDRs specificfor an antigen) has the ability to recognize and bind antigen, althoughat a lower affinity than the entire binding site.

[0184] The Fab fragment also contains the constant domain of the lightchain and the first constant domain (CH1) of the heavy chain. Fabfragments differ from Fab′ fragments by the addition of a few residuesat the carboxy terminus of the heavy chain CH1 domain including one ormore cysteines from the antibody hinge region. Fab′-SH is thedesignation herein for Fab′ in which the cysteine residue(s) of theconstant domains bear a free thiol group. F(ab′)₂ antibody fragmentsoriginally were produced as pairs of Fab′ fragments which have hingecysteines between them. Other chemical couplings of antibody fragmentsare also known.

[0185] The “light chains” of antibodies (immunoglobulins) from anyvertebrate species can be assigned to one of two clearly distinct types,called kappa and lambda, based on the amino acid sequences of theirconstant domains.

[0186] Depending on the amino acid sequence of the constant domain oftheir heavy chains, immunoglobulins can be assigned to differentclasses. There are five major classes of immunoglobulins: IgA, IgD, IgE,IgG, and IgM, and several of these may be further divided intosubclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA, and IgA2.

[0187] “Single-chain Fv” or “sFv” antibody fragments comprise the V_(H)and V_(L) domains of antibody, wherein these domains are present in asingle polypeptide chain. Preferably, the Fv polypeptide furthercomprises a polypeptide linker between the V_(H) and V_(L) domains whichenables the sFv to form the desired structure for antigen binding. For areview of sFv, see Pluckthun in The Pharmacology of MonoclonalAntibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, NewYork, pp. 269-315 (1994).

[0188] The term “diabodies” refers to small antibody fragments with twoantigen-binding sites, which fragments comprise a heavy-chain variabledomain (V_(H)) connected to a light-chain variable domain (V_(L)) in thesame polypeptide chain (V_(H)-V_(L)). By using a linker that is tooshort to allow pairing between the two domains on the same chain, thedomains are forced to pair with the complementary domains of anotherchain and create two antigen-binding sites. Diabodies are described morefully in, for example, EP 404,097; WO 93/11161; and Hollinger et al.,Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993).

[0189] An “isolated” antibody is one which has been identified andseparated and/or recovered from a component of its natural environment.Contaminant components of its natural environment are materials whichwould interfere with diagnostic or therapeutic uses for the antibody,and may include enzymes, hormones, and other proteinaceous ornonproteinaceous solutes. In preferred embodiments, the antibody will bepurified (1) to greater than 95% by weight of antibody as determined bythe Lowry method, and most preferably more than 99% by weight, (2) to adegree sufficient to obtain at least 15 residues of N-terminal orinternal amino acid sequence by use of a spinning cup sequenator, or (3)to homogeneity by SDS-PAGE under reducing or nonreducing conditionsusing Coomassie blue or, preferably, silver stain. Isolated antibodyincludes the antibody in situ within recombinant cells since at leastone component of the antibody's natural environment will not be present.Ordinarily, however, isolated antibody will be prepared by at least onepurification step.

[0190] An antibody that “specifically binds to” or is “specific for” aparticular polypeptide or an epitope on a particular polypeptide is onethat binds to that particular polypeptide or epitope on a particularpolypeptide without substantially binding to any other polypeptide orpolypeptide epitope.

[0191] The word “label” when used herein refers to a detectable compoundor composition which is conjugated directly or indirectly to theantibody so as to generate a “labeled” antibody. The label may bedetectable by itself (e.g. radioisotope labels or fluorescent labels)or, in the case of an enzymatic label, may catalyze chemical alterationof a substrate compound or composition which is detectable.

[0192] By “solid phase” is meant a non-aqueous matrix to which theantibody of the present invention can adhere. Examples of solid phasesencompassed herein include those formed partially or entirely of glass(e.g., controlled pore glass), polysaccharides (e.g., agarose),polyacrylamides, polystyrene, polyvinyl alcohol and silicones. Incertain embodiments, depending on the context, the solid phase cancomprise the well of an assay plate; in others it is a purificationcolumn (e.g., an affinity chromatography column). This term alsoincludes a discontinuous solid phase of discrete particles, such asthose described in U.S. Pat. No. 4,275,149.

[0193] A “liposome” is a small vesicle composed of various types oflipids, phospholipids and/or surfactant which is useful for delivery ofa drug (such as a PRO polypeptide or antibody thereto) to a mammal. Thecomponents of the liposome are commonly arranged in a bilayer formation,similar to the lipid arrangement of biological membranes.

[0194] A “small molecule” is defined herein to have a molecular weightbelow about 500 Daltons.

[0195] An “effective amount” of a polypeptide disclosed herein or anagonist or antagonist thereof is an amount sufficient to carry out aspecifically stated purpose. An “effective amount” may be determinedempirically and in a routine manner, in relation to the stated purpose.

TABLE 2 PRO XXXXXXXXXXXXXXX (Length = 15 amino acids) ComparisonXXXXXYYYYYYY (Length = 12 amino acids) Protein

[0196] TABLE 3 PRO XXXXXXXXXX (Length = 10 amino acids) ComparisonXXXXXYYYYYYZZYZ (Length = 15 amino acids) Protein

[0197] TABLE 4 PRO-DNA NNNNNNNNNNNNNN (Length = 14 nucleotides)Comparison NNNNNNLLLLLLLLLL (Length = 16 nucleotides) DNA

[0198] TABLE 5 PRO-DNA NNNNNNNNNNNN (Length = 12 nucleotides) ComparisonDNA NNNNLLLVV (Length = 9 nucleotides)

[0199] II. Compositions and Methods of the Invention

[0200] A. Full-Length PRO Polypeptides

[0201] The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in the presentapplication as PRO polypeptides. In particular, cDNAs encoding variousPRO polypeptides have been identified and isolated, as disclosed infurther detail in the Examples below. It is noted that proteins producedin separate expression rounds may be given different PRO numbers but theUNQ number is unique for any given DNA and the encoded protein, and willnot be changed. However, for sake of simplicity, in the presentspecification the protein encoded by the full length native nucleic acidmolecules disclosed herein as well as all further native homologues andvariants included in the foregoing definition of PRO, will be referredto as “PRO/number”, regardless of their origin or mode of preparation.

[0202] As disclosed in the Examples below, various cDNA clones have beendeposited with the ATCC. The actual nucleotide sequences of those clonescan readily be determined by the skilled artisan by sequencing of thedeposited clone using routine methods in the art. The predicted aminoacid sequence can be determined from the nucleotide sequence usingroutine skill. For the PRO polypeptides and encoding nucleic acidsdescribed herein, Applicants have identified what is believed to be thereading frame best identifiable with the sequence information availableat the time.

[0203] B. PRO Polypeptide Variants

[0204] In addition to the full-length native sequence PRO polypeptidesdescribed herein, it is contemplated that PRO variants can be prepared.PRO variants can be prepared by introducing appropriate nucleotidechanges into the PRO DNA, and/or by synthesis of the desired PROpolypeptide. Those skilled in the art will appreciate that amino acidchanges may alter post-translational processes of the PRO, such aschanging the number or position of glycosylation sites or altering themembrane anchoring characteristics.

[0205] Variations in the native full-length sequence PRO or in variousdomains of the PRO described herein, can be made, for example, using anyof the techniques and guidelines for conservative and non-conservativemutations set forth, for instance, in U.S. Pat. No. 5,364,934.Variations may be a substitution, deletion or insertion of one or morecodons encoding the PRO that results in a change in the amino acidsequence of the PRO as compared with the native sequence PRO. Optionallythe variation is by substitution of at least one amino acid with anyother amino acid in one or more of the domains of the PRO. Guidance indetermining which amino acid residue may be inserted, substituted ordeleted without adversely affecting the desired activity may be found bycomparing the sequence of the PRO with that of homologous known proteinmolecules and minimizing the number of amino acid sequence changes madein regions of high homology. Amino acid substitutions can be the resultof replacing one amino acid with another amino acid having similarstructural and/or chemical properties, such as the replacement of aleucine with a serine, i.e., conservative amino acid replacements.Insertions or deletions may optionally be in the range of about 1 to 5amino acids. The variation allowed may be determined by systematicallymaking insertions, deletions or substitutions of amino acids in thesequence and testing the resulting variants for activity exhibited bythe full-length or mature native sequence.

[0206] PRO polypeptide fragments are provided herein. Such fragments maybe truncated at the N-terminus or C-terminus, or may lack internalresidues, for example, when compared with a full length native protein.Certain fragments lack amino acid residues that are not essential for adesired biological activity of the PRO polypeptide.

[0207] PRO fragments may be prepared by any of a number of conventionaltechniques. Desired peptide fragments may be chemically synthesized. Analternative approach involves generating PRO fragments by enzymaticdigestion, e.g., by treating the protein with an enzyme known to cleaveproteins at sites defined by particular amino acid residues, or bydigesting the DNA with suitable restriction enzymes and isolating thedesired fragment. Yet another suitable technique involves isolating andamplifying a DNA fragment encoding a desired polypeptide fragment, bypolymerase chain reaction (PCR). Oligonucleotides that define thedesired termini of the DNA fragment are employed at the 5′ and 3′primers in the PCR. Preferably, PRO polypeptide fragments share at leastone biological and/or immunological activity with the native PROpolypeptide disclosed herein.

[0208] In particular embodiments, conservative substitutions of interestare shown in Table 6 under the heading of preferred substitutions. Ifsuch substitutions result in a change in biological activity, then moresubstantial changes, denominated exemplary substitutions in Table 6, oras further described below in reference to amino acid classes, areintroduced and the products screened. TABLE 6 Original ExemplaryPreferred Residue Substitutions Substitutions Ala (A) val; leu; ile valArg (R) lys; gln; asn lys Asn (N) gln; his; lys; arg gln Asp (D) glu gluCys (C) ser ser Gln (Q) asn asn Glu (E) asp asp Gly (G) pro; ala ala His(H) asn; gln; lys; arg arg Ile (I) leu; val; met; ala; phe; leunorleucine Leu (L) norleucine; ile; val; ile met; ala; phe Lys (K) arg;gln; asn arg Met (M) leu; phe; ile leu Phe (F) leu; val; ile; ala; tyrleu Pro (P) ala ala Ser (S) thr thr Thr (T) ser ser Trp (W) tyr; phe tyrTyr (Y) trp; phe; thr; ser phe Val (V) ile; leu; met; phe; leu ala;norleucine

[0209] Substantial modifications in function or immunological identityof the PRO polypeptide are accomplished by selecting substitutions thatdiffer significantly in their effect on maintaining (a) the structure ofthe polypeptide backbone in the area of the substitution, for example,as a sheet or helical conformation, (b) the charge or hydrophobicity ofthe molecule at the target site, or (c) the bulk of the side chain.Naturally occurring residues are divided into groups based on commonside-chain properties:

[0210] (1) hydrophobic: norleucine, met, ala, val, leu, ile;

[0211] (2) neutral hydrophilic: cys, ser, thr;

[0212] (3) acidic: asp, glu;

[0213] (4) basic: asn, gln, his, lys, arg;

[0214] (5) residues that influence chain orientation: gly, pro; and

[0215] (6) aromatic: trp, tyr, phe.

[0216] Non-conservative substitutions will entail exchanging a member ofone of these classes for another class. Such substituted residues alsomay be introduced into the conservative substitution sites or, morepreferably, into the remaining (non-conserved) sites.

[0217] The variations can be made using methods known in the art such asoligonucleotide-mediated (site-directed) mutagenesis, alanine scanning,and PCR mutagenesis. Site-directed mutagenesis [Carter et al., Nucl.Acids Res., 13:4331 (1986); Zoller et al., Nucl. Acids Res., 10:6487(1987)], cassette mutagenesis [Wells et al., Gene, 34:315 (1985)],restriction selection mutagenesis [Wells et al., Philos. Trans. R. Soc.London SerA, 317:415 (1986)] or other known techniques can be performedon the cloned DNA to produce the PRO variant DNA.

[0218] Scanning amino acid analysis can also be employed to identify oneor more amino acids along a contiguous sequence. Among the preferredscanning amino acids are relatively small, neutral amino acids. Suchamino acids include alanine, glycine, serine, and cysteine. Alanine istypically a preferred scanning amino acid among this group because iteliminates the side-chain beyond the beta-carbon and is less likely toalter the main-chain conformation of the variant [Cunningham and Wells,Science, 244: 1081-1085 (1989)]. Alanine is also typically preferredbecause it is the most common amino acid. Further, it is frequentlyfound in both buried and exposed positions [Creighton, The Proteins,(W.H. Freeman & Co., N.Y.); Chothia, J. Mol. Biol., 150:1 (1976)]. Ifalanine substitution does not yield adequate amounts of variant, anisoteric amino acid can be used.

[0219] C. Modifications of PRO

[0220] Covalent modifications of PRO are included within the scope ofthis invention. One type of covalent modification includes reactingtargeted amino acid residues of a PRO polypeptide with an organicderivatizing agent that is capable of reacting with selected side chainsor the N- or C-terminal residues of the PRO. Derivatization withbifunctional agents is useful, for instance, for crosslinking PRO to awater-insoluble support matrix or surface for use in the method forpurifying anti-PRO antibodies, and vice-versa. Commonly usedcrosslinking agents include, e.g., 1,1-bis(diazoacetyl)-2-phenylethane,glutaraldehyde, N-hydroxysuccinimide esters, for example, esters with4-azidosalicylic acid, homobifunctional imidoesters, includingdisuccinimidyl esters such as 3,3′-dithiobis(succinimidylpropionate),bifunctional maleimides such as bis-N-maleimido-1,8-octane and agentssuch as methyl-3-[(p-azidophenyl)dithio]propioimidate.

[0221] Other modifications include deamidation of glutaminyl andasparaginyl residues to the corresponding glutamyl and aspartylresidues, respectively, hydroxylation of proline and lysine,phosphorylation of hydroxyl groups of seryl or threonyl residues,methylation of the α-amino groups of lysine, arginine, and histidineside chains [T. E. Creighton, Proteins: Structure and MolecularProperties, W.H. Freeman & Co., San Francisco, pp. 79-86 (1983)],acetylation of the N-terminal amine, and amidation of any C-terminalcarboxyl group.

[0222] Another type of covalent modification of the PRO polypeptideincluded within the scope of this invention comprises altering thenative glycosylation pattern of the polypeptide. “Altering the nativeglycosylation pattern” is intended for purposes herein to mean deletingone or more carbohydrate moieties found in native sequence PRO (eitherby removing the underlying glycosylation site or by deleting theglycosylation by chemical and/or enzymatic means), and/or adding one ormore glycosylation sites that are not present in the native sequencePRO. In addition, the phrase includes qualitative changes in theglycosylation of the native proteins, involving a change in the natureand proportions of the various carbohydrate moieties present.

[0223] Addition of glycosylation sites to the PRO polypeptide may beaccomplished by altering the amino acid sequence. The alteration may bemade, for example, by the addition of, or substitution by, one or moreserine or threonine residues to the native sequence PRO (for O-linkedglycosylation sites). The PRO amino acid sequence may optionally bealtered through changes at the DNA level, particularly by mutating theDNA encoding the PRO polypeptide at preselected bases such that codonsare generated that will translate into the desired amino acids.

[0224] Another means of increasing the number of carbohydrate moietieson the PRO polypeptide is by chemical or enzymatic coupling ofglycosides to the polypeptide. Such methods are described in the art,e.g., in WO 87/05330 published 11 Sep. 1987, and in Aplin and Wriston,CRC Crit. Rev. Biochem., pp. 259-306 (1981).

[0225] Removal of carbohydrate moieties present on the PRO polypeptidemay be accomplished chemically or enzymatically or by mutationalsubstitution of codons encoding for amino acid residues that serve astargets for glycosylation. Chemical deglycosylation techniques are knownin the art and described, for instance, by Hakimuddin, et al., Arch.Biochem. Biophys., 259:52 (1987) and by Edge et al., Anal. Biochem.,118:131 (1981). Enzymatic cleavage of carbohydrate moieties onpolypeptides can be achieved by the use of a variety of endo- andexo-glycosidases as described by Thotakura et al., Meth. Enzymol.,138:350 (1987).

[0226] Another type of covalent modification of PRO comprises linkingthe PRO polypeptide to one of a variety of nonproteinaceous polymers,e.g., polyethylene glycol (PEG), polypropylene glycol, orpolyoxyalkylenes, in the manner set forth in U.S. Pat. Nos. 4,640,835;4,496,689; 4,301,144; 4,670,417; 4,791,192 or 4,179,337.

[0227] The PRO of the present invention may also be modified in a way toform a chimeric molecule comprising PRO fused to another, heterologouspolypeptide or amino acid sequence.

[0228] In one embodiment, such a chimeric molecule comprises a fusion ofthe PRO with a tag polypeptide which provides an epitope to which ananti-tag antibody can selectively bind. The epitope tag is generallyplaced at the amino- or carboxyl-terminus of the PRO. The presence ofsuch epitope-tagged forms of the PRO can be detected using an antibodyagainst the tag polypeptide. Also, provision of the epitope tag enablesthe PRO to be readily purified by affinity purification using ananti-tag antibody or another type of affinity matrix that binds to theepitope tag. Various tag polypeptides and their respective antibodiesare well known in the art. Examples include poly-histidine (poly-his) orpoly-histidine-glycine (poly-his-gly) tags; the flu HA tag polypeptideand its antibody 12CA5 [Field et al., Mol. Cell. Biol., 8:2159-2165(1988)]; the c-myc tag and the 8F9, 3C7, 6E10, G4, B7 and 9E10antibodies thereto [Evan et al., Molecular and Cellular Biology,5:3610-3616 (1985)]; and the Herpes Simplex virus glycoprotein D (gD)tag and its antibody [Paborsky et al., Protein Engineering, 3(6):547-553(1990)]. Other tag polypeptides include the Flag-peptide [Hopp et al.,BioTechnology, 6:1204-1210 (1988)]; the KT3 epitope peptide [Martin etal., Science, 255:192-194 (1992)]; an α-tubulin epitope peptide [Skinneret al., J. Biol. Chem., 266:15163-15166 (1991)]; and the T7 gene 10protein peptide tag [Lutz-Freyermuth et al., Proc. Natl. Acad. Sci. USA,87:6393-6397 (1990)].

[0229] In an alternative embodiment, the chimeric molecule may comprisea fusion of the PRO with an immunoglobulin or a particular region of animmunoglobulin. For a bivalent form of the chimeric molecule (alsoreferred to as an “immunoadhesin”), such a fusion could be to the Fcregion of an IgG molecule. The Ig fusions preferably include thesubstitution of a soluble (transmembrane domain deleted or inactivated)form of a PRO polypeptide in place of at least one variable regionwithin an Ig molecule. In a particularly preferred embodiment, theimmunoglobulin fusion includes the hinge, CH2 and CH3, or the hinge,CH1, CH2 and CH3 regions of an IgG1 molecule. For the production ofimmunoglobulin fusions see also U.S. Pat. No. 5,428,130 issued Jun. 27,1995.

[0230] D. Preparation of PRO

[0231] The description below relates primarily to production of PRO byculturing cells transformed or transfected with a vector containing PROnucleic acid. It is, of course, contemplated that alternative methods,which are well known in the art, may be employed to prepare PRO. Forinstance, the PRO sequence, or portions thereof, may be produced bydirect peptide synthesis using solid-phase techniques [see, e.g.,Stewart et al., Solid-Phase Peptide Synthesis, W.H. Freeman Co., SanFrancisco, Calif. (1969); Merrifield, J. Am. Chem. Soc., 85:2149-2154(1963)]. In vitro protein synthesis may be performed using manualtechniques or by automation. Automated synthesis may be accomplished,for instance, using an Applied Biosystems Peptide Synthesizer (FosterCity, Calif.) using manufacturer's instructions. Various portions of thePRO may be chemically synthesized separately and combined using chemicalor enzymatic methods to produce the full-length PRO.

[0232] 1. Isolation of DNA Encoding PRO

[0233] DNA encoding PRO may be obtained from a cDNA library preparedfrom tissue believed to possess the PRO mRNA and to express it at adetectable level. Accordingly, human PRO DNA can be convenientlyobtained from a cDNA library prepared from human tissue, such asdescribed in the Examples. The PRO-encoding gene may also be obtainedfrom a genomic library or by known synthetic procedures (e.g., automatednucleic acid synthesis).

[0234] Libraries can be screened with probes (such as antibodies to thePRO or oligonucleotides of at least about 20-80 bases) designed toidentify the gene of interest or the protein encoded by it. Screeningthe cDNA or genomic library with the selected probe may be conductedusing standard procedures, such as described in Sambrook et al.,Molecular Cloning: A Laboratory Manual (New York: Cold Spring HarborLaboratory Press, 1989). An alternative means to isolate the geneencoding PRO is to use PCR methodology [Sambrook et al., supra;Dieffenbach et al., PCR Primer: A Laboratory Manual (Cold Spring HarborLaboratory Press, 1995)].

[0235] The Examples below describe techniques for screening a cDNAlibrary. The oligonucleotide sequences selected as probes should be ofsufficient length and sufficiently unambiguous that false positives areminimized. The oligonucleotide is preferably labeled such that it can bedetected upon hybridization to DNA in the library being screened.Methods of labeling are well known in the art, and include the use ofradiolabels like ³²P-labeled ATP, biotinylation or enzyme labeling.Hybridization conditions, including moderate stringency and highstringency, are provided in Sambrook et al., supra.

[0236] Sequences identified in such library screening methods can becompared and aligned to other known sequences deposited and available inpublic databases such as GenBank or other private sequence databases.Sequence identity (at either the amino acid or nucleotide level) withindefined regions of the molecule or across the full-length sequence canbe determined using methods known in the art and as described herein.

[0237] Nucleic acid having protein coding sequence may be obtained byscreening selected cDNA or genomic libraries using the deduced aminoacid sequence disclosed herein for the first time, and, if necessary,using conventional primer extension procedures as described in Sambrooket al., supra, to detect precursors and processing intermediates of mRNAthat may not have been reverse-transcribed into cDNA.

[0238] 2. Selection and Transformation of Host Cells

[0239] Host cells are transfected or transformed with expression orcloning vectors described herein for PRO production and cultured inconventional nutrient media modified as appropriate for inducingpromoters, selecting transformants, or amplifying the genes encoding thedesired sequences. The culture conditions, such as media, temperature,pH and the like, can be selected by the skilled artisan without undueexperimentation. In general, principles, protocols, and practicaltechniques for maximizing the productivity of cell cultures can be foundin Mammalian Cell Biotechnology: a Practical Approach, M. Butler, ed.(IRL Press, 1991) and Sambrook et al., supra.

[0240] Methods of eukaryotic cell transfection and prokaryotic celltransformation are known to the ordinarily skilled artisan, for example,CaCl₂, CaPO₄, liposome-mediated and electroporation. Depending on thehost cell used, transformation is performed using standard techniquesappropriate to such cells. The calcium treatment employing calciumchloride, as described in Sambrook et al., supra, or electroporation isgenerally used for prokaryotes. Infection with Agrobacterium tumefaciensis used for transformation of certain plant cells, as described by Shawet al., Gene, 23:315 (1983) and WO 89/05859 published 29 Jun. 1989. Formammalian cells without such cell walls, the calcium phosphateprecipitation method of Graham and van der Eb, Virology, 52:456-457(1978) can be employed. General aspects of mammalian cell host systemtransfections have been described in U.S. Pat. No. 4,399,216.Transformations into yeast are typically carried out according to themethod of Van Solingen et al., J. Bact., 130:946 (1977) and Hsiao etal., Proc. Natl. Acad. Sci. (USA), 76:3829 (1979). However, othermethods for introducing DNA into cells, such as by nuclearmicroinjection, electroporation, bacterial protoplast fusion with intactcells, or polycations, e.g., polybrene, polyornithine, may also be used.For various techniques for transforming mammalian cells, see Keown etal., Methods in Enzymology, 185:527-537 (1990) and Mansour et al.,Nature, 336:348-352 (1988).

[0241] Suitable host cells for cloning or expressing the DNA in thevectors herein include prokaryote, yeast, or higher eukaryote cells.Suitable prokaryotes include but are not limited to eubacteria, such asGram-negative or Gram-positive organisms, for example,Enterobacteriaceae such as E. coli. Various E. coli strains are publiclyavailable, such as E. coli K12 strain MM294 (ATCC 31,446); E. coli X1776(ATCC 31,537); E. coli strain W3110 (ATCC 27,325) and K5 772 (ATCC53,635). Other suitable prokaryotic host cells includeEnterobacteriaceae such as Escherichia, e.g., E. coli, Enterobacter,Erwinia, Klebsiella, Proteus, Salmonella, e.g., Salmonella typhimurium,Serratia, e.g., Serratia marcescans, and Shigella, as well as Bacillisuch as B. subtilis and B. licheniformis (e.g., B. licheniformis 41Pdisclosed in DD 266,710 published 12 Apr. 1989), Pseudomonas such as P.aeruginosa, and Streptomyces. These examples are illustrative ratherthan limiting. Strain W3 110 is one particularly preferred host orparent host because it is a common host strain for recombinant DNAproduct fermentations. Preferably, the host cell secretes minimalamounts of proteolytic enzymes. For example, strain W3110 may bemodified to effect a genetic mutation in the genes encoding proteinsendogenous to the host, with examples of such hosts including E. coliW3110 strain 1A2, which has the complete genotype tonA; E. coli W3110strain 9E4, which has the complete genotype tonA ptr3; E. coli W3110strain 27C7 (ATCC 55,244), which has the complete genotype tonA ptr3phoA E15 (argF-lac)169 degP ompT kan^(r) ; E. coli W3110 strain 37D6,which has the complete genotype tonA ptr3 phoA E15 (argF-lac)169 degPompT rbs7 ilvG kan^(r) ; E. coli W3110 strain 40B4, which is strain 37D6with a non-kanamycin resistant degP deletion mutation; and an E. colistrain having mutant periplasmic protease disclosed in U.S. Pat. No.4,946,783 issued 7 Aug. 1990. Alternatively, in vitro methods ofcloning, e.g., PCR or other nucleic acid polymerase reactions, aresuitable.

[0242] In addition to prokaryotes, eukaryotic microbes such asfilamentous fungi or yeast are suitable cloning or expression hosts forPRO-encoding vectors. Saccharomyces cerevisiae is a commonly used lowereukaryotic host microorganism. Others include Schizosaccharomyces pombe(Beach and Nurse, Nature, 290: 140 [1981]; EP 139,383 published 2 May1985); Kluyveromyces hosts (U.S. Pat. No. 4,943,529; Fleer et al.,Bio/Technology, 9:968-975 (1991)) such as, e.g., K. lactis (MW98-8C,CBS683, CBS4574; Louvencourt et al., J. Bacteriol., 154(2):737-742[1983]), K. fragilis (ATCC 12,424), K. bulgaricus (ATCC 16,045), K.wickeramii (ATCC 24,178), K. waltii (ATCC 56,500), K. drosophilarum(ATCC 36,906; Van den Berg et al., Bio/Technology, 8:135 (1990)), K.thermotolerans, and K. marxianus; yarrowia (EP 402,226); Pichia pastoris(EP 183,070; Sreekrishna et al., J. Basic Microbiol., 28:265-278[1988]); Candida; 7) Trichodema reesia (EP 244,234); Neurospora crassa(Case et al., Proc. Natl. Acad. Sci. USA, 76:5259-5263 [1979]);Schwanniomyces such as Schwanniomyces occidentalis (EP 394,538 published31 Oct. 1990); and filamentous fungi such as, e.g., Neurospora,Penicillium, Tolypocladium (WO 91/00357 published 10 Jan. 1991), andAspergillus hosts such as A. nidulans (Ballance et al., Biochem.Biophys. Res. Commun., 112:284-289 [1983]; Tilburn et al., Gene,26:205-221 [1983]; Yelton et al., Proc. Natl. Acad. Sci. USA, 81:1470-1474 [1984]) and A. niger (Kelly and Hynes, EMBO J., 4:475-479[1985]). Methylotropic yeasts are suitable herein and include, but arenot limited to, yeast capable of growth on methanol selected from thegenera consisting of Hansenula, Candida, Kloeckera, Pichia,Saccharomyces, Torulopsis, and Rhodotorula. A list of specific speciesthat are exemplary of this class of yeasts may be found in C. Anthony,The Biochemistry of Methylotrophs, 269 (1982).

[0243] Suitable host cells for the expression of glycosylated PRO arederived from multicellular organisms. Examples of invertebrate cellsinclude insect cells such as Drosophila S2 and Spodoptera Sf9, as wellas plant cells. Examples of useful mammalian host cell lines includeChinese hamster ovary (CHO) and COS cells. More specific examplesinclude monkey kidney CV1 line transformed by SV40 (COS-7, ATCC CRL1651); human embryonic kidney line (293 or 293 cells subcloned forgrowth in suspension culture, Graham et al., J. Gen Virol., 36:59(1977)); Chinese hamster ovary cells/-DHFR (CHO, Urlaub and Chasin,Proc. Natl. Acad. Sci. USA, 77:4216 (1980)); mouse sertoli cells (TM4,Mather, Biol. Reprod., 23:243-251 (1980)); human lung cells (W138 ATCCCCL 75); human liver cells (Hep G2, HB 8065); and mouse mammary tumor(MMT 060562, ATCC CCL51). The selection of the appropriate host cell isdeemed to be within the skill in the art.

[0244] 3. Selection and Use of a Replicable Vector

[0245] The nucleic acid (e.g., cDNA or genomic DNA) encoding PRO may beinserted into a replicable vector for cloning (amplification of the DNA)or for expression. Various vectors are publicly available. The vectormay, for example, be in the form of a plasmid, cosmid, viral particle,or phage. The appropriate nucleic acid sequence may be inserted into thevector by a variety of procedures. In general, DNA is inserted into anappropriate restriction endonuclease site(s) using techniques known inthe art. Vector components generally include, but are not limited to,one or more of a signal sequence, an origin of replication, one or moremarker genes, an enhancer element, a promoter, and a transcriptiontermination sequence. Construction of suitable vectors containing one ormore of these components employs standard ligation techniques which areknown to the skilled artisan.

[0246] The PRO may be produced recombinantly not only directly, but alsoas a fusion polypeptide with a heterologous polypeptide, which may be asignal sequence or other polypeptide having a specific cleavage site atthe N-terminus of the mature protein or polypeptide. In general, thesignal sequence may be a component of the vector, or it may be a part ofthe PRO-encoding DNA that is inserted into the vector. The signalsequence may be a prokaryotic signal sequence selected, for example,from the group of the alkaline phosphatase, penicillinase, 1pp, orheat-stable enterotoxin II leaders. For yeast secretion the signalsequence may be, e.g., the yeast invertase leader, alpha factor leader(including Saccharomyces and Kluyveromyces α-factor leaders, the latterdescribed in U.S. Pat. No. 5,010,182), or acid phosphatase leader, theC. albicans glucoamylase leader (EP 362,179 published 4 Apr. 1990), orthe signal described in WO 90/13646 published 15 Nov. 1990. In mammaliancell expression, mammalian signal sequences may be used to directsecretion of the protein, such as signal sequences from secretedpolypeptides of the same or related species, as well as viral secretoryleaders.

[0247] Both expression and cloning vectors contain a nucleic acidsequence that enables the vector to replicate in one or more selectedhost cells. Such sequences are well known for a variety of bacteria,yeast, and viruses. The origin of replication from the plasmid pBR322 issuitable for most Gram-negative bacteria, the 2μ plasmid origin issuitable for yeast, and various viral origins (SV40, polyoma,adenovirus, VSV or BPV) are useful for cloning vectors in mammaliancells.

[0248] Expression and cloning vectors will typically contain a selectiongene, also termed a selectable marker. Typical selection genes encodeproteins that (a) confer resistance to antibiotics or other toxins,e.g., ampicillin, neomycin, methotrexate, or tetracycline, (b)complement auxotrophic deficiencies, or (c) supply critical nutrientsnot available from complex media, e.g., the gene encoding D-alanineracemase for Bacilli.

[0249] An example of suitable selectable markers for mammalian cells arethose that enable the identification of cells competent to take up thePRO-encoding nucleic acid, such as DHFR or thymidine kinase. Anappropriate host cell when wild-type DHFR is employed is the CHO cellline deficient in DHFR activity, prepared and propagated as described byUrlaub et al., Proc. Natl. Acad. Sci. USA, 77:4216 (1980). A suitableselection gene for use in yeast is the trp1 gene present in the yeastplasmid YRp7 [Stinchcomb et al., Nature, 282:39 (1979); Kingsman et al.,Gene, 7:141 (1979); Tschemper et al., Gene, 10:157 (1980)]. The trp1gene provides a selection marker for a mutant strain of yeast lackingthe ability to grow in tryptophan, for example, ATCC No. 44076 or PEP4-1[Jones, Genetics, 85:12 (1977)].

[0250] Expression and cloning vectors usually contain a promoteroperably linked to the PRO-encoding nucleic acid sequence to direct mRNAsynthesis. Promoters recognized by a variety of potential host cells arewell known. Promoters suitable for use with prokaryotic hosts includethe P-lactamase and lactose promoter systems [Chang et al., Nature,275:615 (1978); Goeddel et al., Nature, 281:544 (1979)], alkalinephosphatase, a tryptophan (trp) promoter system [Goeddel, Nucleic AcidsRes., 8:4057 (1980); EP 36,776], and hybrid promoters such as the tacpromoter [deBoer et al., Proc. Natl. Acad. Sci. USA, 80:21-25 (1983)].Promoters for use in bacterial systems also will contain aShine-Dalgarno (S.D.) sequence operably linked to the DNA encoding PRO.

[0251] Examples of suitable promoting sequences for use with yeast hostsinclude the promoters for 3-phosphoglycerate kinase [Hitzeman et al., J.Biol. Chem., 255:2073 (1980)] or other glycolytic enzymes [Hess et al.,J. Adv. Enzyme Reg., 7:149 (1968); Holland, Biochemistry, 17:4900(1978)], such as enolase, glyceraldehyde-3-phosphate dehydrogenase,hexokinase, pyruvate decarboxylase, phosphofructokinase,glucose-6-phosphate isomerase, 3-phosphoglycerate mutase, pyruvatekinase, triosephosphate isomerase, phosphoglucose isomerase, andglucokinase.

[0252] Other yeast promoters, which are inducible promoters having theadditional advantage of transcription controlled by growth conditions,are the promoter regions for alcohol dehydrogenase 2, isocytochrome C,acid phosphatase, degradative enzymes associated with nitrogenmetabolism, metallothionein, glyceraldehyde-3-phosphate dehydrogenase,and enzymes responsible for maltose and galactose utilization. Suitablevectors and promoters for use in yeast expression are further describedin EP 73,657.

[0253] PRO transcription from vectors in mammalian host cells iscontrolled, for example, by promoters obtained from the genomes ofviruses such as polyoma virus, fowlpox virus (UK 2,211,504 published 5Jul. 1989), adenovirus (such as Adenovirus 2), bovine papilloma virus,avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis-B virusand Simian Virus 40 (SV40), from heterologous mammalian promoters, e.g.,the actin promoter or an immunoglobulin promoter, and from heat-shockpromoters, provided such promoters are compatible with the host cellsystems.

[0254] Transcription of a DNA encoding the PRO by higher eukaryotes maybe increased by inserting an enhancer sequence into the vector.Enhancers are cis-acting elements of DNA, usually about from 10 to 300bp, that act on a promoter to increase its transcription. Many enhancersequences are now known from mammalian genes (globin, elastase, albumin,α-fetoprotein, and insulin). Typically, however, one will use anenhancer from a eukaryotic cell virus. Examples include the SV40enhancer on the late side of the replication origin (bp 100-270), thecytomegalovirus early promoter enhancer, the polyoma enhancer on thelate side of the replication origin, and adenovirus enhancers. Theenhancer may be spliced into the vector at a position 5′ or 3′ to thePRO coding sequence, but is preferably located at a site 5′ from thepromoter.

[0255] Expression vectors used in eukaryotic host cells (yeast, fungi,insect, plant, animal, human, or nucleated cells from othermulticellular organisms) will also contain sequences necessary for thetermination of transcription and for stabilizing the mRNA. Suchsequences are commonly available from the 5′ and, occasionally 3′,untranslated regions of eukaryotic or viral DNAs or cDNAs. These regionscontain nucleotide segments transcribed as polyadenylated fragments inthe untranslated portion of the mRNA encoding PRO.

[0256] Still other methods, vectors, and host cells suitable foradaptation to the synthesis of PRO in recombinant vertebrate cellculture are described in Gething et al., Nature, 293:620-625 (1981);Mantei et al., Nature, 281:40-46 (1979); EP 117,060; and EP 117,058.

[0257] 4. Detecting Gene Amplification/Expression

[0258] Gene amplification and/or expression may be measured in a sampledirectly, for example, by conventional Southern blotting, Northernblotting to quantitate the transcription of mRNA [Thomas, Proc. Natl.Acad. Sci. USA, 77:5201-5205 (1980)], dot blotting (DNA analysis), or insitu hybridization, using an appropriately labeled probe, based on thesequences provided herein. Alternatively, antibodies may be employedthat can recognize specific duplexes, including DNA duplexes, RNAduplexes, and DNA-RNA hybrid duplexes or DNA-protein duplexes. Theantibodies in turn may be labeled and the assay may be carried out wherethe duplex is bound to a surface, so that upon the formation of duplexon the surface, the presence of antibody bound to the duplex can bedetected.

[0259] Gene expression, alternatively, may be measured by immunologicalmethods, such as immunohistochemical staining of cells or tissuesections and assay of cell culture or body fluids, to quantitatedirectly the expression of gene product. Antibodies useful forimmunohistochemical staining and/or assay of sample fluids may be eithermonoclonal or polyclonal, and may be prepared in any mammal.Conveniently, the antibodies may be prepared against a native sequencePRO polypeptide or against a synthetic peptide based on the DNAsequences provided herein or against exogenous sequence fused to PRO DNAand encoding a specific antibody epitope.

[0260] 5. Purification of Polypeptide

[0261] Forms of PRO may be recovered from culture medium or from hostcell lysates. If membrane-bound, it can be released from the membraneusing a suitable detergent solution (e.g. Triton-X 100) or by enzymaticcleavage. Cells employed in expression of PRO can be disrupted byvarious physical or chemical means, such as freeze-thaw cycling,sonication, mechanical disruption, or cell lysing agents.

[0262] It may be desired to purify PRO from recombinant cell proteins orpolypeptides. The following procedures are exemplary of suitablepurification procedures: by fractionation on an ion-exchange column;ethanol precipitation; reverse phase HPLC; chromatography on silica oron a cation-exchange resin such as DEAE; chromatofocusing; SDS-PAGE;ammonium sulfate precipitation; gel filtration using, for example,Sephadex G-75; protein A Sepharose columns to remove contaminants suchas IgG; and metal chelating columns to bind epitope-tagged forms of thePRO. Various methods of protein purification may be employed and suchmethods are known in the art and described for example in Deutscher,Methods in Enzymology, 182 (1990); Scopes, Protein Purification:Principles and Practice, Springer-Verlag, New York (1982). Thepurification step(s) selected will depend, for example, on the nature ofthe production process used and the particular PRO produced.

[0263] E. Uses for PRO

[0264] Nucleotide sequences (or their complement) encoding PRO havevarious applications in the art of molecular biology, including uses ashybridization probes, in chromosome and gene mapping and in thegeneration of anti-sense RNA and DNA. PRO nucleic acid will also beuseful for the preparation of PRO polypeptides by the recombinanttechniques described herein.

[0265] The full-length native sequence PRO gene, or portions thereof,may be used as hybridization probes for a cDNA library to isolate thefull-length PRO cDNA or to isolate still other cDNAs (for instance,those encoding naturally-occurring variants of PRO or PRO from otherspecies) which have a desired sequence identity to the native PROsequence disclosed herein. Optionally, the length of the probes will beabout 20 to about 50 bases. The hybridization probes may be derived fromat least partially novel regions of the full length native nucleotidesequence wherein those regions may be determined without undueexperimentation or from genomic sequences including promoters, enhancerelements and introns of native sequence PRO. By way of example, ascreening method will comprise isolating the coding region of the PROgene using the known DNA sequence to synthesize a selected probe ofabout 40 bases. Hybridization probes may be labeled by a variety oflabels, including radionucleotides such as ³²P or ³⁵S, or enzymaticlabels such as alkaline phosphatase coupled to the probe viaavidin/biotin coupling systems. Labeled probes having a sequencecomplementary to that of the PRO gene of the present invention can beused to screen libraries of human cDNA, genomic DNA or mRNA to determinewhich members of such libraries the probe hybridizes to. Hybridizationtechniques are described in further detail in the Examples below.

[0266] Any EST sequences disclosed in the present application maysimilarly be employed as probes, using the methods disclosed herein.

[0267] Other useful fragments of the PRO nucleic acids include antisenseor sense oligonucleotides comprising a singe-stranded nucleic acidsequence (either RNA or DNA) capable of binding to target PRO mRNA(sense) or PRO DNA (antisense) sequences. Antisense or senseoligonucleotides, according to the present invention, comprise afragment of the coding region of PRO DNA. Such a fragment generallycomprises at least about 14 nucleotides, preferably from about 14 to 30nucleotides. The ability to derive an antisense or a senseoligonucleotide, based upon a cDNA sequence encoding a given protein isdescribed in, for example, Stein and Cohen (Cancer Res. 48:2659, 1988)and van der Krol et al. (BioTechniques 6:958, 1988).

[0268] Binding of antisense or sense oligonucleotides to target nucleicacid sequences results in the formation of duplexes that blocktranscription or translation of the target sequence by one of severalmeans, including enhanced degradation of the duplexes, prematuretermination of transcription or translation, or by other means. Theantisense oligonucleotides thus may be used to block expression of PROproteins. Antisense or sense oligonucleotides further compriseoligonucleotides having modified sugar-phosphodiester backbones (orother sugar linkages, such as those described in WO 91/06629) andwherein such sugar linkages are resistant to endogenous nucleases. Sucholigonucleotides with resistant sugar linkages are stable in vivo (i.e.,capable of resisting enzymatic degradation) but retain sequencespecificity to be able to bind to target nucleotide sequences.

[0269] Other examples of sense or antisense oligonucleotides includethose oligonucleotides which are covalently linked to organic moieties,such as those described in WO 90/10048, and other moieties thatincreases affinity of the oligonucleotide for a target nucleic acidsequence, such as poly-(L-lysine). Further still, intercalating agents,such as ellipticine, and alkylating agents or metal complexes may beattached to sense or antisense oligonucleotides to modify bindingspecificities of the antisense or sense oligonucleotide for the targetnucleotide sequence.

[0270] Antisense or sense oligonucleotides may be introduced into a cellcontaining the target nucleic acid sequence by any gene transfer method,including, for example, CaPO₄-mediated DNA transfection,electroporation, or by using gene transfer vectors such as Epstein-Barrvirus. In a preferred procedure, an antisense or sense oligonucleotideis inserted into a suitable retroviral vector. A cell containing thetarget nucleic acid sequence is contacted with the recombinantretroviral vector, either in vivo or ex vivo. Suitable retroviralvectors include, but are not limited to, those derived from the murineretrovirus M-MuLV, N2 (a retrovirus derived from M-MuLV), or the doublecopy vectors designated DCT5A, DCT5B and DCT5C (see WO 90/13641).

[0271] Sense or antisense oligonucleotides also may be introduced into acell containing the target nucleotide sequence by formation of aconjugate with a ligand binding molecule, as described in WO 91/04753.Suitable ligand binding molecules include, but are not limited to, cellsurface receptors, growth factors, other cytokines, or other ligandsthat bind to cell surface receptors. Preferably, conjugation of theligand binding molecule does not substantially interfere with theability of the ligand binding molecule to bind to its correspondingmolecule or receptor, or block entry of the sense or antisenseoligonucleotide or its conjugated version into the cell.

[0272] Alternatively, a sense or an antisense oligonucleotide may beintroduced into a cell containing the target nucleic acid sequence byformation of an oligonucleotide-lipid complex, as described in WO90/10448. The sense or antisense oligonucleotide-lipid complex ispreferably dissociated within the cell by an endogenous lipase.

[0273] Antisense or sense RNA or DNA molecules are generally at leastabout 5 bases in length, about 10 bases in length, about 15 bases inlength, about 20 bases in length, about 25 bases in length, about 30bases in length, about 35 bases in length, about 40 bases in length,about 45 bases in length, about 50 bases in length, about 55 bases inlength, about 60 bases in length, about 65 bases in length, about 70bases in length, about 75 bases in length, about 80 bases in length,about 85 bases in length, about 90 bases in length, about 95 bases inlength, about 100 bases in length, or more.

[0274] The probes may also be employed in PCR techniques to generate apool of sequences for identification of closely related PRO codingsequences.

[0275] Nucleotide sequences encoding a PRO can also be used to constructhybridization probes for mapping the gene which encodes that PRO and forthe genetic analysis of individuals with genetic disorders. Thenucleotide sequences provided herein may be mapped to a chromosome andspecific regions of a chromosome using known techniques, such as in situhybridization, linkage analysis against known chromosomal markers, andhybridization screening with libraries.

[0276] When the coding sequences for PRO encode a protein which binds toanother protein (example, where the PRO is a receptor), the PRO can beused in assays to identify the other proteins or molecules involved inthe binding interaction. By such methods, inhibitors of thereceptor/ligand binding interaction can be identified. Proteins involvedin such binding interactions can also be used to screen for peptide orsmall molecule inhibitors or agonists of the binding interaction. Also,the receptor PRO can be used to isolate correlative ligand(s). Screeningassays can be designed to find lead compounds that mimic the biologicalactivity of a native PRO or a receptor for PRO. Such screening assayswill include assays amenable to high-throughput screening of chemicallibraries, making them particularly suitable for identifying smallmolecule drug candidates. Small molecules contemplated include syntheticorganic or inorganic compounds. The assays can be performed in a varietyof formats, including protein-protein binding assays, biochemicalscreening assays, immunoassays and cell based assays, which are wellcharacterized in the art.

[0277] Nucleic acids which encode PRO or its modified forms can also beused to generate either transgenic animals or “knock out” animals which,in turn, are useful in the development and screening of therapeuticallyuseful reagents. A transgenic animal (e.g., a mouse or rat) is an animalhaving cells that contain a transgene, which transgene was introducedinto the animal or an ancestor of the animal at a prenatal, e.g., anembryonic stage. A transgene is a DNA which is integrated into thegenome of a cell from which a transgenic)animal develops. In oneembodiment, cDNA encoding PRO can be used to clone genomic DNA encodingPRO in accordance with established techniques and the genomic sequencesused to generate transgenic animals that contain cells which express DNAencoding PRO. Methods for generating transgenic animals, particularlyanimals such as mice or rats, have become conventional in the art andare described, for example, in U.S. Pat. Nos. 4,736,866 and 4,870,009.Typically, particular cells would be targeted for PRO transgeneincorporation with tissue-specific enhancers. Transgenic animals thatinclude a copy of a transgene encoding PRO introduced into the germ lineof the animal at an embryonic stage can be used to examine the effect ofincreased expression of DNA encoding PRO. Such animals can be used astester animals for reagents thought to confer protection from, forexample, pathological conditions associated with its overexpression. Inaccordance with this facet of the invention, an animal is treated withthe reagent and a reduced incidence of the pathological condition,compared to untreated animals bearing the transgene, would indicate apotential therapeutic intervention for the pathological condition.

[0278] Alternatively, non-human homologues of PRO can be used toconstruct a PRO “knock out” animal which has a defective or altered geneencoding PRO as a result of homologous recombination between theendogenous gene encoding PRO and altered genomic DNA encoding PROintroduced into an embryonic stem cell of the animal. For example, cDNAencoding PRO can be used to clone genomic DNA encoding PRO in accordancewith established techniques. A portion of the genomic DNA encoding PROcan be deleted or replaced with another gene, such as a gene encoding aselectable marker which can be used to monitor integration. Typically,several kilobases of unaltered flanking DNA (both at the 5′ and 3′ ends)are included in the vector [see e.g., Thomas and Capecchi, Cell, 51:503(1987) for a description of homologous recombination vectors]. Thevector is introduced into an embryonic stem cell line (e.g., byelectroporation) and cells in which the introduced DNA has homologouslyrecombined with the endogenous DNA are selected [see e.g., Li et al.,Cell, 69:915 (1992)]. The selected cells are then injected into ablastocyst of an animal (e.g., a mouse or rat) to form aggregationchimeras [see e.g., Bradley, in Teratocarcinomas and Embryonic StemCells: A Practical Approach, E. J. Robertson, ed. (IRL, Oxford, 1987),pp. 113-152]. A chimeric embryo can then be implanted into a suitablepseudopregnant female foster animal and the embryo brought to term tocreate a “knock out” animal. Progeny harboring the homologouslyrecombined DNA in their germ cells can be identified by standardtechniques and used to breed animals in which all cells of the animalcontain the homologously recombined DNA. Knockout animals can becharacterized for instance, for their ability to defend against certainpathological conditions and for their development of pathologicalconditions due to absence of the PRO polypeptide.

[0279] Nucleic acid encoding the PRO polypeptides may also be used ingene therapy. In gene therapy applications, genes are introduced intocells in order to achieve in vivo synthesis of a therapeuticallyeffective genetic product, for example for replacement of a defectivegene. “Gene therapy” includes both conventional gene therapy where alasting effect is achieved by a single treatment, and the administrationof gene therapeutic agents, which involves the one time or repeatedadministration of a therapeutically effective DNA or mRNA. AntisenseRNAs and DNAs can be used as therapeutic agents for blocking theexpression of certain genes in vivo. It has already been shown thatshort antisense oligonucleotides can be imported into cells where theyact as inhibitors, despite their low intracellular concentrations causedby their restricted uptake by the cell membrane. (Zamecnik et al., Proc.Natl. Acad. Sci. USA 83:4143-4146 [1986]). The oligonucleotides can bemodified to enhance their uptake, e.g. by substituting their negativelycharged phosphodiester groups by uncharged groups.

[0280] There are a variety of techniques available for introducingnucleic acids into viable cells. The techniques vary depending uponwhether the nucleic acid is transferred into cultured cells in vitro, orin vivo in the cells of the intended host. Techniques suitable for thetransfer of nucleic acid into mammalian cells in vitro include the useof liposomes, electroporation, microinjection, cell fusion,DEAE-dextran, the calcium phosphate precipitation method, etc. Thecurrently preferred in vivo gene transfer techniques includetransfection with viral (typically retroviral) vectors and viral coatprotein-liposome mediated transfection (Dzau et al., Trends inBiotechnology 11, 205-210 [1993]). In some situations it is desirable toprovide the nucleic acid source with an agent that targets the targetcells, such as an antibody specific for a cell surface membrane proteinor the target cell, a ligand for a receptor on the target cell, etc.Where liposomes are employed, proteins which bind to a cell surfacemembrane protein associated with endocytosis may be used for targetingand/or to facilitate uptake, e.g. capsid proteins or fragments thereoftropic for a particular cell type, antibodies for proteins which undergointernalization in cycling, proteins that target intracellularlocalization and enhance intracellular half-life. The technique ofreceptor-mediated endocytosis is described, for example, by Wu et al.,J. Biol. Chem. 262, 4429-4432 (1987); and Wagner et al., Proc. Natl.Acad. Sci. USA 87, 3410-3414 (1990). For review of gene marking and genetherapy protocols see Anderson et al., Science 256, 808-813 (1992).

[0281] The PRO polypeptides described herein may also be employed asmolecular weight markers for protein electrophoresis purposes and theisolated nucleic acid sequences may be used for recombinantly expressingthose markers.

[0282] The nucleic acid molecules encoding the PRO polypeptides orfragments thereof described herein are useful for chromosomeidentification. In this regard, there exists an ongoing need to identifynew chromosome markers, since relatively few chromosome markingreagents, based upon actual sequence data are presently available. EachPRO nucleic acid molecule of the present invention can be used as achromosome marker.

[0283] The PRO polypeptides and nucleic acid molecules of the presentinvention may also be used diagnostically for tissue typing, wherein thePRO polypeptides of the present invention may be differentiallyexpressed in one tissue as compared to another, preferably in a diseasedtissue as compared to a normal tissue of the same tissue type. PROnucleic acid molecules will find use for generating probes for PCR,Northern analysis, Southern analysis and Western analysis.

[0284] The PRO polypeptides described herein may also be employed astherapeutic agents. The PRO polypeptides of the present invention can beformulated according to known methods to prepare pharmaceutically usefulcompositions, whereby the PRO product hereof is combined in admixturewith a pharmaceutically acceptable carrier vehicle. Therapeuticformulations are prepared for storage by mixing the active ingredienthaving the desired degree of purity with optional physiologicallyacceptable carriers, excipients or stabilizers (Remington'sPharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the formof lyophilized formulations or aqueous solutions. Acceptable carriers,excipients or stabilizers are nontoxic to recipients at the dosages andconcentrations employed, and include buffers such as phosphate, citrateand other organic acids; antioxidants including ascorbic acid; lowmolecular weight (less than about 10 residues) polypeptides; proteins,such as serum albumin, gelatin or immunoglobulins; hydrophilic polymerssuch as polyvinylpyrrolidone, amino acids such as glycine, glutamine,asparagine, arginine or lysine; monosaccharides, disaccharides and othercarbohydrates including glucose, mannose, or dextrins; chelating agentssuch as EDTA; sugar alcohols such as mannitol or sorbitol; salt-formingcounterions such as sodium; and/or nonionic surfactants such as TWEEN™,PLURONICS™ or PEG.

[0285] The formulations to be used for in vivo administration must besterile. This is readily accomplished by filtration through sterilefiltration membranes, prior to or following lyophilization andreconstitution.

[0286] Therapeutic compositions herein generally are placed into acontainer having a sterile access port, for example, an intravenoussolution bag or vial having a stopper pierceable by a hypodermicinjection needle.

[0287] The route of administration is in accord with known methods, e.g.injection or infusion by intravenous, intraperitoneal, intracerebral,intramuscular, intraocular, intraarterial or intralesional routes,topical administration, or by sustained release systems.

[0288] Dosages and desired drug concentrations of pharmaceuticalcompositions of the present invention may vary depending on theparticular use envisioned. The determination of the appropriate dosageor route of administration is well within the skill of an ordinaryphysician. Animal experiments provide reliable guidance for thedetermination of effective doses for human therapy. Interspecies scalingof effective doses can be performed following the principles laid downby Mordenti, J. and Chappell, W. “The use of interspecies scaling intoxicokinetics” In Toxicokinetics and New Drug Development, Yacobi etal., Eds., Pergamon Press, New York 1989, pp. 42-96.

[0289] When in vivo administration of a PRO polypeptide or agonist orantagonist thereof is employed, normal dosage amounts may vary fromabout 10 ng/kg to up to 100 mg/kg of mammal body weight or more per day,preferably about 1 μg/kg/day to 10 mg/kg/day, depending upon the routeof administration. Guidance as to particular dosages and methods ofdelivery is provided in the literature; see, for example, U.S. Pat. Nos.4,657,760; 5,206,344; or 5,225,212. It is anticipated that differentformulations will be effective for different treatment compounds anddifferent disorders, that administration targeting one organ or tissue,for example, may necessitate delivery in a manner different from that toanother organ or tissue.

[0290] Where sustained-release administration of a PRO polypeptide isdesired in a formulation with release characteristics suitable for thetreatment of any disease or disorder requiring administration of the PROpolypeptide, microencapsulation of the PRO polypeptide is contemplated.Microencapsulation of recombinant proteins for sustained release hasbeen successfully performed with human growth hormone (rhGH),interferon-(rhIFN-), interleukin-2, and MN rgp120. Johnson et al., Nat.Med., 2:795-799 (1996); Yasuda, Biomed. Ther., 27:1221-1223 (1993); Horaet al., Bio/Technology, 8:755-758 (1990); Cleland, “Design andProduction of Single Immunization Vaccines Using PolylactidePolyglycolide Microsphere Systems,” in Vaccine Design: The Subunit andAdjuvant Approach, Powell and Newman, eds, (Plenum Press: New York,1995), pp. 439-462; WO 97/03692, WO 96/40072, WO 96/07399; and U.S. Pat.No. 5,654,010.

[0291] The sustained-release formulations of these proteins weredeveloped using poly-lactic-coglycolic acid (PLGA) polymer due to itsbiocompatibility and wide range of biodegradable properties. Thedegradation products of PLGA, lactic and glycolic acids, can be clearedquickly within the human body. Moreover, the degradability of thispolymer can be adjusted from months to years depending on its molecularweight and composition. Lewis, “Controlled release of bioactive agentsfrom lactide/glycolide polymer,” in: M. Chasin and R. Langer (Eds.),Biodegradable Polymers as Drug Delivery Systems (Marcel Dekker: NewYork, 1990), pp. 1-41.

[0292] This invention encompasses methods of screening compounds toidentify those that mimic the PRO polypeptide (agonists) or prevent theeffect of the PRO polypeptide (antagonists). Screening assays forantagonist drug candidates are designed to identify compounds that bindor complex with the PRO polypeptides encoded by the genes identifiedherein, or otherwise interfere with the interaction of the encodedpolypeptides with other cellular proteins. Such screening assays willinclude assays amenable to high-throughput screening of chemicallibraries, making them particularly suitable for identifying smallmolecule drug candidates.

[0293] The assays can be performed in a variety of formats, includingprotein-protein binding assays, biochemical screening assays,immunoassays, and cell-based assays, which are well characterized in theart.

[0294] All assays for antagonists are common in that they call forcontacting the drug candidate with a PRO polypeptide encoded by anucleic acid identified herein under conditions and for a timesufficient to allow these two components to interact.

[0295] In binding assays, the interaction is binding and the complexformed can be isolated or detected in the reaction mixture. In aparticular embodiment, the PRO polypeptide encoded by the geneidentified herein or the drug candidate is immobilized on a solid phase,e.g., on a microtiter plate, by covalent or non-covalent attachments.Non-covalent attachment generally is accomplished by coating the solidsurface with a solution of the PRO polypeptide and drying.Alternatively, an immobilized antibody, e.g., a monoclonal antibody,specific for the PRO polypeptide to be immobilized can be used to anchorit to a solid surface. The assay is performed by adding thenon-immobilized component, which may be labeled by a detectable label,to the immobilized component, e.g., the coated surface containing theanchored component. When the reaction is complete, the non-reactedcomponents are removed, e.g., by washing, and complexes anchored on thesolid surface are detected. When the originally non-immobilizedcomponent carries a detectable label, the detection of label immobilizedon the surface indicates that complexing occurred. Where the originallynon-immobilized component does not carry a label, complexing can bedetected, for example, by using a labeled antibody specifically bindingthe immobilized complex.

[0296] If the candidate compound interacts with but does not bind to aparticular PRO polypeptide encoded by a gene identified herein, itsinteraction with that polypeptide can be assayed by methods well knownfor detecting protein-protein interactions. Such assays includetraditional approaches, such as, e.g., cross-linking,co-immunoprecipitation, and co-purification through gradients orchromatographic columns. In addition, protein-protein interactions canbe monitored by using a yeast-based genetic system described by Fieldsand co-workers (Fields and Song, Nature (London), 340:245-246(1989);Chien et al., Proc. Natl. Acad. Sci. USA, 88:9578-9582 (1991)) asdisclosed by Chevray and Nathans, Proc. Natl. Acad. Sci. USA, 89:5789-5793 (1991). Many transcriptional activators, such as yeast GAL4,consist of two physically discrete modular domains, one acting as theDNA-binding domain, the other one functioning as thetranscription-activation domain. The yeast expression system describedin the foregoing publications (generally referred to as the “two-hybridsystem”) takes advantage of this property, and employs two hybridproteins, one in which the target protein is fused to the DNA-bindingdomain of GAL4, and another, in which candidate activating proteins arefused to the activation domain. The expression of a GAL1-lacZ reportergene under control of a GAL4-activated promoter depends onreconstitution of GAL4 activity via protein-protein interaction.Colonies containing interacting polypeptides are detected with achromogenic substrate for P-galactosidase. A complete kit (MATCHMAKER™)for identifying protein-protein interactions between two specificproteins using the two-hybrid technique is commercially available fromClontech. This system can also be extended to map protein domainsinvolved in specific protein interactions as well as to pinpoint aminoacid residues that are crucial for these interactions.

[0297] Compounds that interfere with the interaction of a gene encodinga PRO polypeptide identified herein and other intra- or extracellularcomponents can be tested as follows: usually a reaction mixture isprepared containing the product of the gene and the intra- orextracellular component under conditions and for a time allowing for theinteraction and binding of the two products. To test the ability of acandidate compound to inhibit binding, the reaction is run in theabsence and in the presence of the test compound. In addition, a placebomay be added to a third reaction mixture, to serve as positive control.The binding (complex formation) between the test compound and the intra-or extracellular component present in the mixture is monitored asdescribed hereinabove. The formation of a complex in the controlreaction(s) but not in the reaction mixture containing the test compoundindicates that the test compound interferes with the interaction of thetest compound and its reaction partner.

[0298] To assay for antagonists, the PRO polypeptide may be added to acell along with the compound to be screened for a particular activityand the ability of the compound to inhibit the activity of interest inthe presence of the PRO polypeptide indicates that the compound is anantagonist to the PRO polypeptide. Alternatively, antagonists may bedetected by combining the PRO polypeptide and a potential antagonistwith membrane-bound PRO polypeptide receptors or recombinant receptorsunder appropriate conditions for a competitive inhibition assay. The PROpolypeptide can be labeled, such as by radioactivity, such that thenumber of PRO polypeptide molecules bound to the receptor can be used todetermine the effectiveness of the potential antagonist. The geneencoding the receptor can be identified by numerous methods known tothose of skill in the art, for example, ligand panning and FACS sorting.Coligan et al., Current Protocols in Immun., 1(2): Chapter 5 (1991).Preferably, expression cloning is employed wherein polyadenylated RNA isprepared from a cell responsive to the PRO polypeptide and a cDNAlibrary created from this RNA is divided into pools and used totransfect COS cells or other cells that are not responsive to the PROpolypeptide. Transfected cells that are grown on glass slides areexposed to labeled PRO polypeptide. The PRO polypeptide can be labeledby a variety of means including iodination or inclusion of a recognitionsite for a site-specific protein kinase. Following fixation andincubation, the slides are subjected to autoradiographic analysis.Positive pools are identified and sub-pools are prepared andre-transfected using an interactive sub-pooling and re-screeningprocess, eventually yielding a single clone that encodes the putativereceptor.

[0299] As an alternative approach for receptor identification, labeledPRO polypeptide can be photoaffinity-linked with cell membrane orextract preparations that express the receptor molecule. Cross-linkedmaterial is resolved by PAGE and exposed to X-ray film. The labeledcomplex containing the receptor can be excised, resolved into peptidefragments, and subjected to protein micro-sequencing. The amino acidsequence obtained from micro-sequencing would be used to design a set ofdegenerate oligonucleotide probes to screen a cDNA library to identifythe gene encoding the putative receptor.

[0300] In another assay for antagonists, mammalian cells or a membranepreparation expressing the receptor would be incubated with labeled PROpolypeptide in the presence of the candidate compound. The ability ofthe compound to enhance or block this interaction could then bemeasured.

[0301] More specific examples of potential antagonists include anoligonucleotide that binds to the fusions of immunoglobulin with PROpolypeptide, and, in particular, antibodies including, withoutlimitation, poly- and monoclonal antibodies and antibody fragments,single-chain antibodies, anti-idiotypic antibodies, and chimeric orhumanized versions of such antibodies or fragments, as well as humanantibodies and antibody fragments. Alternatively, a potential antagonistmay be a closely related protein, for example, a mutated form of the PROpolypeptide that recognizes the receptor but imparts no effect, therebycompetitively inhibiting the action of the PRO polypeptide.

[0302] Another potential PRO polypeptide antagonist is an antisense RNAor DNA construct prepared using antisense technology, where, e.g., anantisense RNA or DNA molecule acts to block directly the translation ofmRNA by hybridizing to targeted mRNA and preventing protein translation.Antisense technology can be used to control gene expression throughtriple-helix formation or antisense DNA or RNA, both of which methodsare based on binding of a polynucleotide to DNA or RNA. For example, the5′ coding portion of the polynucleotide sequence, which encodes themature PRO polypeptides herein, is used to design an antisense RNAoligonucleotide of from about 10 to 40 base pairs in length. A DNAoligonucleotide is designed to be complementary to a region of the geneinvolved in transcription (triple helix—see Lee et al., Nucl. AcidsRes., 6:3073 (1979); Cooney et al., Science, 241: 456(1988); Dervan etal., Science, 251:1360(1991)), thereby preventing transcription and theproduction of the PRO polypeptide. The antisense RNA oligonucleotidehybridizes to the mRNA in vivo and blocks translation of the mRNAmolecule into the PRO polypeptide (antisense—Okano, Neurochem., 56:560(1991); Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression(CRC Press: Boca Raton, Fla., 1988). The oligonucleotides describedabove can also be delivered to cells such that the antisense RNA or DNAmay be expressed in vivo to inhibit production of the PRO polypeptide.When antisense DNA is used, oligodeoxyribonucleotides derived from thetranslation-initiation site, e.g., between about −10 and +10 positionsof the target gene nucleotide sequence, are preferred.

[0303] Potential antagonists include small molecules that bind to theactive site, the receptor binding site, or growth factor or otherrelevant binding site of the PRO polypeptide, thereby blocking thenormal biological activity of the PRO polypeptide. Examples of smallmolecules include, but are not limited to, small peptides orpeptide-like molecules, preferably soluble peptides, and syntheticnon-peptidyl organic or inorganic compounds.

[0304] Ribozymes are enzymatic RNA molecules capable of catalyzing thespecific cleavage of RNA. Ribozymes act by sequence-specifichybridization to the complementary target RNA, followed byendonucleolytic cleavage. Specific ribozyme cleavage sites within apotential RNA target can be identified by known techniques. For furtherdetails see, e.g., Rossi, Current Biology, 4:469-471 (1994), and PCTpublication No. WO 97/33551 (published Sep. 18, 1997).

[0305] Nucleic acid molecules in triple-helix formation used to inhibittranscription should be single-stranded and composed ofdeoxynucleotides. The base composition of these oligonucleotides isdesigned such that it promotes triple-helix formation via Hoogsteenbase-pairing rules, which generally require sizeable stretches ofpurines or pyrimidines on one strand of a duplex. For further detailssee, e.g., PCT publication No. WO 97/33551, supra.

[0306] These small molecules can be identified by any one or more of thescreening assays discussed hereinabove and/or by any other screeningtechniques well known for those skilled in the art.

[0307] Diagnostic and therapeutic uses of the herein disclosed moleculesmay also be based upon the positive functional assay hits disclosed anddescribed below.

[0308] F. Anti-PRO Antibodies

[0309] The present invention further provides anti-PRO antibodies.Exemplary antibodies include polyclonal, monoclonal, humanized,bispecific, and heteroconjugate antibodies.

[0310] 1. Polyclonal Antibodies

[0311] The anti-PRO antibodies may comprise polyclonal antibodies.Methods of preparing polyclonal antibodies are known to the skilledartisan. Polyclonal antibodies can be raised in a mammal, for example,by one or more injections of an immunizing agent and, if desired, anadjuvant. Typically, the immunizing agent and/or adjuvant will beinjected in the mammal by multiple subcutaneous or intraperitonealinjections. The immunizing agent may include the PRO polypeptide or afusion protein thereof. It may be useful to conjugate the immunizingagent to a protein known to be immunogenic in the mammal beingimmunized. Examples of such immunogenic proteins include but are notlimited to keyhole limpet hemocyanin, serum albumin, bovinethyroglobulin, and soybean trypsin inhibitor. Examples of adjuvantswhich may be employed include Freund's complete adjuvant and MPL-TDMadjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate).The immunization protocol may be selected by one skilled in the artwithout undue experimentation.

[0312] 2. Monoclonal Antibodies

[0313] The anti-PRO antibodies may, alternatively, be monoclonalantibodies. Monoclonal antibodies may be prepared using hybridomamethods, such as those described by Kohler and Milstein, Nature, 256:495(1975). In a hybridoma method, a mouse, hamster, or other appropriatehost animal, is typically immunized with an immunizing agent to elicitlymphocytes that produce or are capable of producing antibodies thatwill specifically bind to the immunizing agent. Alternatively, thelymphocytes may be immunized in vitro.

[0314] The immunizing agent will typically include the PRO polypeptideor a fusion protein thereof. Generally, either peripheral bloodlymphocytes (“PBLs”) are used if cells of human origin are desired, orspleen cells or lymph node cells are used if non-human mammalian sourcesare desired. The lymphocytes are then fused with an immortalized cellline using a suitable fusing agent, such as polyethylene glycol, to forma hybridoma cell [Goding, Monoclonal Antibodies: Principles andPractice, Academic Press, (1986) pp. 59-103]. Immortalized cell linesare usually transformed mammalian cells, particularly myeloma cells ofrodent, bovine and human origin. Usually, rat or mouse myeloma celllines are employed. The hybridoma cells may be cultured in a suitableculture medium that preferably contains one or more substances thatinhibit the growth or survival of the unfused, immortalized cells. Forexample, if the parental cells lack the enzyme hypoxanthine guaninephosphoribosyl transferase (HGPRT or HPRT), the culture medium for thehybridomas typically will include hypoxanthine, aminopterin, andthymidine (“HAT medium”), which substances prevent the growth ofHGPRT-deficient cells.

[0315] Preferred immortalized cell lines are those that fuseefficiently, support stable high level expression of antibody by theselected antibody-producing cells, and are sensitive to a medium such asHAT medium. More preferred immortalized cell lines are murine myelomalines, which can be obtained, for instance, from the Salk Institute CellDistribution Center, San Diego, Calif. and the American Type CultureCollection, Manassas, Va. Human myeloma and mouse-human heteromyelomacell lines also have been described for the production of humanmonoclonal antibodies [Kozbor, J. Immunol., 133:3001 (1984); Brodeur etal., Monoclonal Antibody Production Techniques and Applications, MarcelDekker, Inc., New York, (1987) pp. 51-63].

[0316] The culture medium in which the hybridoma cells are cultured canthen be assayed for the presence of monoclonal antibodies directedagainst PRO. Preferably, the binding specificity of monoclonalantibodies produced by the hybridoma cells is determined byimmunoprecipitation or by an in vitro binding assay, such asradioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA).Such techniques and assays are known in the art. The binding affinity ofthe monoclonal antibody can, for example, be determined by the Scatchardanalysis of Munson and Pollard, Anal. Biochem., 107:220 (1980).

[0317] After the desired hybridoma cells are identified, the clones maybe subcloned by limiting dilution procedures and grown by standardmethods [Goding, supra]. Suitable culture media for this purposeinclude, for example, Dulbecco's Modified Eagle's Medium and RPMI-1640medium. Alternatively, the hybridoma cells may be grown in vivo asascites in a mammal.

[0318] The monoclonal antibodies secreted by the subclones may beisolated or purified from the culture medium or ascites fluid byconventional immunoglobulin purification procedures such as, forexample, protein A-Sepharose, hydroxylapatite chromatography, gelelectrophoresis, dialysis, or affinity chromatography.

[0319] The monoclonal antibodies may also be made by recombinant DNAmethods, such as those described in U.S. Pat. No. 4,816,567. DNAencoding the monoclonal antibodies of the invention can be readilyisolated and sequenced using conventional procedures (e.g., by usingoligonucleotide probes that are capable of binding specifically to genesencoding the heavy and light chains of murine antibodies). The hybridomacells of the invention serve as a preferred source of such DNA. Onceisolated, the DNA may be placed into expression vectors, which are thentransfected into host cells such as simian COS cells, Chinese hamsterovary (CHO) cells, or myeloma cells that do not otherwise produceimmunoglobulin protein, to obtain the synthesis of monoclonal antibodiesin the recombinant host cells. The DNA also may be modified, forexample, by substituting the coding sequence for human heavy and lightchain constant domains in place of the homologous murine sequences [U.S.Pat. No. 4,816,567; Morrison et al., supra] or by covalently joining tothe immunoglobulin coding sequence all or part of the coding sequencefor a non-immunoglobulin polypeptide. Such a non-immunoglobulinpolypeptide can be substituted for the constant domains of an antibodyof the invention, or can be substituted for the variable domains of oneantigen-combining site of an antibody of the invention to create achimeric bivalent antibody.

[0320] The antibodies may be monovalent antibodies. Methods forpreparing monovalent antibodies are well known in the art. For example,one method involves recombinant expression of immunoglobulin light chainand modified heavy chain. The heavy chain is truncated generally at anypoint in the Fc region so as to prevent heavy chain crosslinking.Alternatively, the relevant cysteine residues are substituted withanother amino acid residue or are deleted so as to prevent crosslinking.

[0321] In vitro methods are also suitable for preparing monovalentantibodies. Digestion of antibodies to produce fragments thereof,particularly, Fab fragments, can be accomplished using routinetechniques known in the art.

[0322] 3. Human and Humanized Antibodies

[0323] The anti-PRO antibodies of the invention may further comprisehumanized antibodies or human antibodies. Humanized forms of non-human(e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulinchains or fragments thereof (such as Fv, Fab, Fab′, F(ab′)₂ or otherantigen-binding subsequences of antibodies) which contain minimalsequence derived from non-human immunoglobulin. Humanized antibodiesinclude human immunoglobulins (recipient antibody) in which residuesfrom a complementary determining region (CDR) of the recipient arereplaced by residues from a CDR of a non-human species (donor antibody)such as mouse, rat or rabbit having the desired specificity, affinityand capacity. In some instances, Fv framework residues of the humanimmunoglobulin are replaced by corresponding non-human residues.Humanized antibodies may also comprise residues which are found neitherin the recipient antibody nor in the imported CDR or frameworksequences. In general, the humanized antibody will comprisesubstantially all of at least one, and typically two, variable domains,in which all or substantially all of the CDR regions correspond to thoseof a non-human immunoglobulin and all or substantially all of the FRregions are those of a human immunoglobulin consensus sequence. Thehumanized antibody optimally also will comprise at least a portion of animmunoglobulin constant region (Fc), typically that of a humanimmunoglobulin [Jones et al., Nature, 321:522-525 (1986); Riechmann etal., Nature, 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol.,2:593-596 (1992)].

[0324] Methods for humanizing non-human antibodies are well known in theart. Generally, a humanized antibody has one or more amino acid residuesintroduced into it from a source which is non-human. These non-humanamino acid residues are often referred to as “import” residues, whichare typically taken from an “import” variable domain. Humanization canbe essentially performed following the method of Winter and co-workers[Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature,332:323-327 (1988); Verhoeyen et al. Science, 239:1534-1536 (1988)], bysubstituting rodent CDRs or CDR sequences for the correspondingsequences of a human antibody. Accordingly, such “humanized” antibodiesare chimeric antibodies (U.S. Pat. No. 4,816,567), wherein substantiallyless than an intact human variable domain has been substituted by thecorresponding sequence from a non-human species. In practice, humanizedantibodies are typically human antibodies in which some CDR residues andpossibly some FR residues are substituted by residues from analogoussites in rodent antibodies.

[0325] Human antibodies can also be produced using various techniquesknown in the art, including phage display libraries [Hoogenboom andWinter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol.,222:581 (1991)]. The techniques of Cole et al. and Boerner et al. arealso available for the preparation of human monoclonal antibodies (Coleet al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77(1985) and Boerner et al., J. Immunol., 147(1):86-95 (1991)]. Similarly,human antibodies can be made by introducing of human immunoglobulin lociinto transgenic animals, e.g., mice in which the endogenousimmunoglobulin genes have been partially or completely inactivated. Uponchallenge, human antibody production is observed, which closelyresembles that seen in humans in all respects, including generearrangement, assembly, and antibody repertoire. This approach isdescribed, for example, in U.S. Pat. Nos. 5,545,807; 5,545,806;5,569,825; 5,625,126; 5,633,425; 5,661,016, and in the followingscientific publications: Marks et al., Bio/Technology 10, 779-783(1992); Lonberg et al., Nature 368 856-859 (1994); Morrison, Nature 368,812-13 (1994); Fishwild et al., Nature Biotechnology 14, 845-51 (1996);Neuberger, Nature Biotechnology 14, 826 (1996); Lonberg and Huszar,Intern. Rev. Immunol. 13 65-93 (1995).

[0326] The antibodies may also be affinity matured using known selectionand/or mutagenesis methods as described above. Preferred affinitymatured antibodies have an affinity which is five times, more preferably10 times, even more preferably 20 or 30 times greater than the startingantibody (generally murine, humanized or human) from which the maturedantibody is prepared.

[0327] 4. Bispecific Antibodies

[0328] Bispecific antibodies are monoclonal, preferably human orhumanized, antibodies that have binding specificities for at least twodifferent antigens. In the present case, one of the bindingspecificities is for the PRO, the other one is for any other antigen,and preferably for a cell-surface protein or receptor or receptorsubunit.

[0329] Methods for making bispecific antibodies are known in the art.Traditionally, the recombinant production of bispecific antibodies isbased on the co-expression of two immunoglobulin heavy-chain/light-chainpairs, where the two heavy chains have different specificities [Milsteinand Cuello, Nature, 305:537-539 (1983)]. Because of the randomassortment of immunoglobulin heavy and light chains, these hybridomas(quadromas) produce a potential mixture of ten different antibodymolecules, of which only one has the correct bispecific structure. Thepurification of the correct molecule is usually accomplished by affinitychromatography steps. Similar procedures are disclosed in WO 93/08829,published 13 May 1993, and in Traunecker et al., EMBO J., 10:3655-3659(1991).

[0330] Antibody variable domains with the desired binding specificities(antibody-antigen combining sites) can be fused to immunoglobulinconstant domain sequences. The fusion preferably is with animmunoglobulin heavy-chain constant domain, comprising at least part ofthe hinge, CH2, and CH3 regions. It is preferred to have the firstheavy-chain constant region (CH1) containing the site necessary forlight-chain binding present in at least one of the fusions. DNAsencoding the immunoglobulin heavy-chain fusions and, if desired, theimmunoglobulin light chain, are inserted into separate expressionvectors, and are co-transfected into a suitable host organism. Forfurther details of generating bispecific antibodies see, for example,Suresh et al., Methods in Enzymology, 121:210 (1986).

[0331] According to another approach described in WO 96/27011, theinterface between a pair of antibody molecules can be engineered tomaximize the percentage of heterodimers which are recovered fromrecombinant cell culture. The preferred interface comprises at least apart of the CH3 region of an antibody constant domain. In this method,one or more small amino acid side chains from the interface of the firstantibody molecule are replaced with larger side chains (e.g. tyrosine ortryptophan). Compensatory “cavities” of identical or similar size to thelarge side chain(s) are created on the interface of the second antibodymolecule by replacing large amino acid side chains with smaller ones(e.g. alanine or threonine). This provides a mechanism for increasingthe yield of the heterodimer over other unwanted end-products such ashomodimers.

[0332] Bispecific antibodies can be prepared as full length antibodiesor antibody fragments (e.g. F(ab′)₂ bispecific antibodies). Techniquesfor generating bispecific antibodies from antibody fragments have beendescribed in the literature. For example, bispecific antibodies can beprepared can be prepared using chemical linkage. Brennan et al., Science229:81 (1985) describe a procedure wherein intact antibodies areproteolytically cleaved to generate F(ab′)₂ fragments. These fragmentsare reduced in the presence of the dithiol complexing agent sodiumarsenite to stabilize vicinal dithiols and prevent intermoleculardisulfide formation. The Fab′ fragments generated are then converted tothionitrobenzoate (TNB) derivatives. One of the Fab′-TNB derivatives isthen reconverted to the Fab′-thiol by reduction with mercaptoethylamineand is mixed with an equimolar amount of the other Fab′-TNB derivativeto form the bispecific antibody. The bispecific antibodies produced canbe used as agents for the selective immobilization of enzymes.

[0333] Fab′ fragments may be directly recovered from E. coli andchemically coupled to form bispecific antibodies. Shalaby et al., J.Exp. Med. 175:217-225 (1992) describe the production of a fullyhumanized bispecific antibody F(ab′)₂ molecule. Each Fab′ fragment wasseparately secreted from E. coli and subjected to directed chemicalcoupling in vitro to form the bispecific antibody. The bispecificantibody thus formed was able to bind to cells overexpressing the ErbB2receptor and normal human T cells, as well as trigger the lytic activityof human cytotoxic lymphocytes against human breast tumor targets.

[0334] Various technique for making and isolating bispecific antibodyfragments directly from recombinant cell culture have also beendescribed. For example, bispecific antibodies have been produced usingleucine zippers. Kostelny et al., J. Immunol. 148(5):1547-1553 (1992).The leucine zipper peptides from the Fos and Jun proteins were linked tothe Fab′ portions of two different antibodies by gene fusion. Theantibody homodimers were reduced at the hinge region to form monomersand then re-oxidized to form the antibody heterodimers. This method canalso be utilized for the production of antibody homodimers. The“diabody” technology described by Hollinger et al., Proc. Natl. Acad.Sci. USA 90:6444-6448 (1993) has provided an alternative mechanism formaking bispecific antibody fragments. The fragments comprise aheavy-chain variable domain (V_(H)) connected to a light-chain variabledomain (V_(L)) by a linker which is too short to allow pairing betweenthe two domains on the same chain. Accordingly, the V_(H) and V_(L)domains of one fragment are forced to pair with the complementary V_(L)and V_(H) domains of another fragment, thereby forming twoantigen-binding sites. Another strategy for making bispecific antibodyfragments by the use of single-chain Fv (sFv) dimers has also beenreported. See, Gruber et al., J. Immunol. 152:5368 (1994). Antibodieswith more than two valencies are contemplated. For example, trispecificantibodies can be prepared. Tutt et al., J. Immunol. 147:60 (1991).

[0335] Exemplary bispecific antibodies may bind to two differentepitopes on a given PRO polypeptide herein. Alternatively, an anti-PROpolypeptide arm may be combined with an arm which binds to a triggeringmolecule on a leukocyte such as a T-cell receptor molecule (e.g. CD2,CD3, CD28, or B7), or Fc receptors for IgG (FcγR), such as FcγRI (CD64),FcγRIII (CD32) and FcγRII (CD 16) so as to focus cellular defensemechanisms to the cell expressing the particular PRO polypeptide.Bispecific antibodies may also be used to localize cytotoxic agents tocells which express a particular PRO polypeptide. These antibodiespossess a PRO-binding arm and an arm which binds a cytotoxic agent or aradionuclide chelator, such as EOTUBE, DPTA, DOTA, or TETA. Anotherbispecific antibody of interest binds the PRO polypeptide and furtherbinds tissue factor (TF).

[0336] 5. Heteroconjugate Antibodies

[0337] Heteroconjugate antibodies are also within the scope of thepresent invention. Heteroconjugate antibodies are composed of twocovalently joined antibodies. Such antibodies have, for example, beenproposed to target immune system cells to unwanted cells [U.S. Pat. No.4,676,980], and for treatment of HIV infection [WO 91/00360; WO92/200373; EP 03089]. It is contemplated that the antibodies may beprepared in vitro using known methods in synthetic protein chemistry,including those involving crosslinking agents. For example, immunotoxinsmay be constructed using a disulfide exchange reaction or by forming athioether bond. Examples of suitable reagents for this purpose includeiminothiolate and methyl-4-mercaptobutyrimidate and those disclosed, forexample, in U.S. Pat. No. 4,676,980.

[0338] 6. Effector Function Engineering

[0339] It may be desirable to modify the antibody of the invention withrespect to effector function, so as to enhance, e.g., the effectivenessof the antibody in treating cancer. For example, cysteine residue(s) maybe introduced into the Fc region, thereby allowing interchain disulfidebond formation in this region. The homodimeric antibody thus generatedmay have improved internalization capability and/or increasedcomplement-mediated cell killing and antibody-dependent cellularcytotoxicity (ADCC). See Caron et al., J. Exp Med., 176: 1191-1195(1992) and Shopes, J. Immunol., 148: 2918-2922 (1992). Homodimericantibodies with enhanced anti-tumor activity may also be prepared usingheterobifunctional cross-linkers as described in Wolff et al. CancerResearch, 53: 2560-2565 (1993). Alternatively, an antibody can beengineered that has dual Fc regions and may thereby have enhancedcomplement lysis and ADCC capabilities. See Stevenson et al.,Anti-Cancer Drug Design, 3: 219-230 (1989).

[0340] 7. Immunoconjugates

[0341] The invention also pertains to immunoconjugates comprising anantibody conjugated to a cytotoxic agent such as a chemotherapeuticagent, toxin (e.g., an enzymatically active toxin of bacterial, fungal,plant, or animal origin, or fragments thereof), or a radioactive isotope(i.e., a radioconjugate).

[0342] Chemotherapeutic agents useful in the generation of suchimmunoconjugates have been described above. Enzymatically active toxinsand fragments thereof that can be used include diphtheria A chain,nonbinding active fragments of diphtheria toxin, exotoxin A chain (fromPseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain,alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolacaamericana proteins (PAPI, PAPII, and PAP-S), momordica charantiainhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin,mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes. Avariety of radionuclides are available for the production ofradioconjugated antibodies. Examples include ²¹²Bi, ¹³¹I, ¹³¹In, ⁹⁰Y,and ¹⁸⁶Re. Conjugates of the antibody and cytotoxic agent are made usinga variety of bifunctional protein-coupling agents such asN-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane(IT), bifunctional derivatives of imidoesters (such as dimethyladipimidate HCL), active esters (such as disuccinimidyl suberate),aldehydes (such as glutareldehyde), bis-azido compounds (such as bis(p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such asbis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such astolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin canbe prepared as described in Vitetta et al., Science, 238: 1098 (1987).Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent forconjugation of radionucleotide to the antibody. See WO94/11026.

[0343] In another embodiment, the antibody may be conjugated to a“receptor” (such streptavidin) for utilization in tumor pretargetingwherein the antibody-receptor conjugate is administered to the patient,followed by removal of unbound conjugate from the circulation using aclearing agent and then administration of a “ligand” (e.g., avidin) thatis conjugated to a cytotoxic agent (e.g., a radionucleotide).

[0344] 8. Immunoliposomes

[0345] The antibodies disclosed herein may also be formulated asimmunoliposomes. Liposomes containing the antibody are prepared bymethods known in the art, such as described in Epstein et al., Proc.Natl. Acad. Sci. USA, 82: 3688 (1985); Hwang et al., Proc. Natl Acad.Sci. USA, 77: 4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545.Liposomes with enhanced circulation time are disclosed in U.S. Pat. No.5,013,556.

[0346] Particularly useful liposomes can be generated by thereverse-phase evaporation method with a lipid composition comprisingphosphatidylcholine, cholesterol, and PEG-derivatizedphosphatidylethanolamine (PEG-PE). Liposomes are extruded throughfilters of defined pore size to yield liposomes with the desireddiameter. Fab′ fragments of the antibody of the present invention can beconjugated to the liposomes as described in Martin et al., J. Biol.Chem., 257: 286-288 (1982) via a disulfide-interchange reaction. Achemotherapeutic agent (such as Doxorubicin) is optionally containedwithin the liposome. See Gabizon et al., J. National Cancer Inst.,81(19): 1484 (1989).

[0347] 9. Pharmaceutical Compositions of Antibodies

[0348] Antibodies specifically binding a PRO polypeptide identifiedherein, as well as other molecules identified by the screening assaysdisclosed hereinbefore, can be administered for the treatment of variousdisorders in the form of pharmaceutical compositions.

[0349] If the PRO polypeptide is intracellular and whole antibodies areused as inhibitors, internalizing antibodies are preferred. However,lipofections or liposomes can also be used to deliver the antibody, oran antibody fragment, into cells. Where antibody fragments are used, thesmallest inhibitory fragment that specifically binds to the bindingdomain of the target protein is preferred. For example, based upon thevariable-region sequences of an antibody, peptide molecules can bedesigned that retain the ability to bind the target protein sequence.Such peptides can be synthesized chemically and/or produced byrecombinant DNA technology. See, e.g., Marasco et al., Proc. Natl. Acad.Sci. USA, 90: 7889-7893 (1993). The formulation herein may also containmore than one active compound as necessary for the particular indicationbeing treated, preferably those with complementary activities that donot adversely affect each other. Alternatively, or in addition, thecomposition may comprise an agent that enhances its function, such as,for example, a cytotoxic agent, cytokine, chemotherapeutic agent, orgrowth-inhibitory agent. Such molecules are suitably present incombination in amounts that are effective for the purpose intended.

[0350] The active ingredients may also be entrapped in microcapsulesprepared, for example, by coacervation techniques or by interfacialpolymerization, for example, hydroxymethylcellulose orgelatin-microcapsules and poly-(methylmethacylate) microcapsules,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles, andnanocapsules) or in macroemulsions. Such techniques are disclosed inRemington's Pharmaceutical Sciences, supra.

[0351] The formulations to be used for in vivo administration must besterile. This is readily accomplished by filtration through sterilefiltration membranes.

[0352] Sustained-release preparations may be prepared. Suitable examplesof sustained-release preparations include semipermeable matrices ofsolid hydrophobic polymers containing the antibody, which matrices arein the form of shaped articles, e.g., films, or microcapsules. Examplesof sustained-release matrices include polyesters, hydrogels (forexample, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)),polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acidand γ ethyl-L-glutamate, non-degradable ethylene-vinyl acetate,degradable lactic acid-glycolic acid copolymers such as the LUPRONDEPOT™ (injectable microspheres composed of lactic acid-glycolic acidcopolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.While polymers such as ethylene-vinyl acetate and lactic acid-glycolicacid enable release of molecules for over 100 days, certain hydrogelsrelease proteins for shorter time periods. When encapsulated antibodiesremain in the body for a long time, they may denature or aggregate as aresult of exposure to moisture at 37° C., resulting in a loss ofbiological activity and possible changes in immunogenicity. Rationalstrategies can be devised for stabilization depending on the mechanisminvolved. For example, if the aggregation mechanism is discovered to beintermolecular S-S bond formation through thio-disulfide interchange,stabilization may be achieved by modifying sulfhydryl residues,lyophilizing from acidic solutions, controlling moisture content, usingappropriate additives, and developing specific polymer matrixcompositions.

[0353] G. Uses for Anti-PRO Antibodies

[0354] The anti-PRO antibodies of the invention have various utilities.For example, anti-PRO antibodies may be used in diagnostic assays forPRO, e.g., detecting its expression (and in some cases, differentialexpression) in specific cells, tissues, or serum. Various diagnosticassay techniques known in the art may be used, such as competitivebinding assays, direct or indirect sandwich assays andimmunoprecipitation assays conducted in either heterogeneous orhomogeneous phases [Zola, Monoclonal Antibodies: A Manual ofTechniques,CRC Press, Inc. (1987) pp. 147-158]. The antibodies used inthe diagnostic assays can be labeled with a detectable moiety. Thedetectable moiety should be capable of producing, either directly orindirectly, a detectable signal. For example, the detectable moiety maybe a radioisotope, such as ³H, ¹⁴C, ³²P, ³⁵S, or ¹²¹I, a fluorescent orchemiluminescent compound, such as fluorescein isothiocyanate,rhodamine, or luciferin, or an enzyme, such as alkaline phosphatase,beta-galactosidase or horseradish peroxidase. Any method known in theart for conjugating the antibody to the detectable moiety may beemployed, including those methods described by Hunter et al., Nature,144:945 (1962); David et al., Biochemistry, 13:1014 (1974); Pain et al.,J. Immunol. Meth., 40:219 (1981); and Nygren, J. Histochem. andCytochem., 30:407 (1982).

[0355] Anti-PRO antibodies also are useful for the affinity purificationof PRO from recombinant cell culture or natural sources. In thisprocess, the antibodies against PRO are immobilized on a suitablesupport, such a Sephadex resin or filter paper, using methods well knownin the art. The immobilized antibody then is contacted with a samplecontaining the PRO to be purified, and thereafter the support is washedwith a suitable solvent that will remove substantially all the materialin the sample except the PRO, which is bound to the immobilizedantibody. Finally, the support is washed with another suitable solventthat will release the PRO from the antibody.

[0356] The following examples are offered for illustrative purposesonly, and are not intended to limit the scope of the present inventionin any way.

[0357] All patent and literature references cited in the presentspecification are hereby incorporated by reference in their entirety.

EXAMPLES

[0358] Commercially available reagents referred to in the examples wereused according to manufacturer's instructions unless otherwiseindicated. The source of those cells identified in the followingexamples, and throughout the specification, by ATCC accession numbers isthe American Type Culture Collection, Manassas, Va.

Example 1 Extracellular Domain Homology Screening to Identify NovelPolypeptides and cDNA Encoding Therefor

[0359] The extracellular domain (ECD) sequences (including the secretionsignal sequence, if any) from about 950 known secreted proteins from theSwiss-Prot public database were used to search EST databases. The ESTdatabases included public databases (e.g., Dayhoff, GenBank), andproprietary databases (e.g. LIFESEQ™, Incyte Pharmaceuticals, Palo Alto,Calif.). The search was performed using the computer program BLAST orBLAST-2 (Altschul et al., Methods in Enzymology, 266:460-480 (1996)) asa comparison of the ECD protein sequences to a 6 frame translation ofthe EST sequences. Those comparisons with a BLAST score of 70 (or insome cases 90) or greater that did not encode known proteins wereclustered and assembled into consensus DNA sequences with the program“phrap” (Phil Green, University of Washington, Seattle, Wash.).

[0360] Using this extracellular domain homology screen, consensus DNAsequences were assembled relative to the other identified EST sequencesusing phrap. In addition, the consensus DNA sequences obtained wereoften (but not always) extended using repeated cycles of BLAST orBLAST-2 and phrap to extend the consensus sequence as far as possibleusing the sources of EST sequences discussed above.

[0361] Based upon the consensus sequences obtained as described above,oligonucleotides were then synthesized and used to identify by PCR acDNA library that contained the sequence of interest and for use asprobes to isolate a clone of the full-length coding sequence for a PROpolypeptide. Forward and reverse PCR primers generally range from 20 to30 nucleotides and are often designed to give a PCR product of about100-1000 bp in length. The probe sequences are typically 40-55 bp inlength. In some cases, additional oligonucleotides are synthesized whenthe consensus sequence is greater than about 1-1.5 kbp. In order toscreen several libraries for a full-length clone, DNA from the librarieswas screened by PCR amplification, as per Ausubel et al., CurrentProtocols in Molecular Biology, with the PCR primer pair. A positivelibrary was then used to isolate clones encoding the gene of interestusing the probe oligonucleotide and one of the primer pairs.

[0362] The cDNA libraries used to isolate the cDNA clones wereconstructed by standard methods using commercially available reagentssuch as those from Invitrogen, San Diego, Calif. The cDNA was primedwith oligo dT containing a NotI site, linked with blunt to SalIhemikinased adaptors, cleaved with NotI, sized appropriately by gelelectrophoresis, and cloned in a defined orientation into a suitablecloning vector (such as pRKB or pRKD; pRK5B is a precursor of pRK5D thatdoes not contain the SfiI site; see, Holmes et al., Science,253:1278-1280 (1991)) in the unique XhoI and NotI sites.

Example 2 Isolation of cDNA Clones by Amylase Screening

[0363] 1. Preparation of Oligo dT Primed cDNA Library

[0364] mRNA was isolated from a human tissue of interest using reagentsand protocols from Invitrogen, San Diego, Calif. (Fast Track 2). ThisRNA was used to generate an oligo dT primed cDNA library in the vectorpRK5D using reagents and protocols from Life Technologies, Gaithersburg,Md. (Super Script Plasmid System). In this procedure, the doublestranded cDNA was sized to greater than 1000 bp and the SalI/NotIlinkered cDNA was cloned into XhoI/NotI cleaved vector. pRK5D is acloning vector that has an sp6 transcription initiation site followed byan SfiI restriction enzyme site preceding the XhoI/NotI cDNA cloningsites.

[0365] 2. Preparation of Random Primed cDNA Library

[0366] A secondary cDNA library was generated in order to preferentiallyrepresent the 5′ ends of the primary cDNA clones. Sp6 RNA was generatedfrom the primary library (described above), and this RNA was used togenerate a random primed cDNA library in the vector pSST-AMY.0 usingreagents and protocols from Life Technologies (Super Script PlasmidSystem, referenced above). In this procedure the double stranded cDNAwas sized to 500-1000 bp, linkered with blunt to NotI adaptors, cleavedwith SfiI, and cloned into SfiI/NotI cleaved vector. pSST-AMY.0 is acloning vector that has a yeast alcohol dehydrogenase promoter precedingthe cDNA cloning sites and the mouse amylase sequence (the maturesequence without the secretion signal) followed by the yeast alcoholdehydrogenase terminator, after the cloning sites. Thus, cDNAs clonedinto this vector that are fused in frame with amylase sequence will leadto the secretion of amylase from appropriately transfected yeastcolonies.

[0367] 3. Transformation and Detection

[0368] DNA from the library described in paragraph 2 above was chilledon ice to which was added electrocompetent DH10B bacteria (LifeTechnologies, 20 ml). The bacteria and vector mixture was thenelectroporated as recommended by the manufacturer. Subsequently, SOCmedia (Life Technologies, 1 ml) was added and the mixture was incubatedat 37° C. for 30 minutes. The transformants were then plated onto 20standard 150 mm LB plates containing ampicillin and incubated for 16hours (37° C.). Positive colonies were scraped off the plates and theDNA was isolated from the bacterial pellet using standard protocols,e.g. CsCl-gradient. The purified DNA was then carried on to the yeastprotocols below.

[0369] The yeast methods were divided into three categories: (1)Transformation of yeast with the plasmid/cDNA combined vector; (2)Detection and isolation of yeast clones secreting amylase; and (3) PCRamplification of the insert directly from the yeast colony andpurification of the DNA for sequencing and further analysis.

[0370] The yeast strain used was HD56-5A (ATCC-90785). This strain hasthe following genotype: MAT alpha, ura3-52, leu2-3, leu2-112, his3-11,his3-15, MAL+, SUC+, GAL+. Preferably, yeast mutants can be employedthat have deficient post-translational pathways. Such mutants may havetranslocation deficient alleles in sec71, sec72, sec62, with truncatedsec71 being most preferred. Alternatively, antagonists (includingantisense nucleotides and/or ligands) which interfere with the normaloperation of these genes, other proteins implicated in this posttranslation pathway (e.g., SEC61p, SEC72p, SEC62p, SEC63p, TDJ1p orSSA1p-4p) or the complex formation of these proteins may also bepreferably employed in combination with the amylase-expressing yeast.

[0371] Transformation was performed based on the protocol outlined byGietz et al., Nucl. Acid. Res., 20:1425 (1992). Transformed cells werethen inoculated from agar into YEPD complex media broth (100 ml) andgrown overnight at 30° C. The YEPD broth was prepared as described inKaiser et al., Methods in Yeast Genetics, Cold Spring Harbor Press, ColdSpring Harbor, N.Y., p. 207 (1994). The overnight culture was thendiluted to about 2×10⁶ cells/ml (approx. OD₆₀₀=0.1) into fresh YEPDbroth (500 ml) and regrown to 1×10⁷ cells/ml (approx. OD₆₀₀=0.4-0.5).

[0372] The cells were then harvested and prepared for transformation bytransfer into GS3 rotor bottles in a Sorval GS3 rotor at 5,000 rpm for 5minutes, the supernatant discarded, and then resuspended into sterilewater, and centrifuged again in 50 ml falcon tubes at 3,500 rpm in aBeckman GS-6KR centrifuge. The supernatant was discarded and the cellswere subsequently washed with LiAc/TE (10 ml, 10 mM Tris-HCl, 1 mM EDTApH 7.5, 100 mM Li₂OOCCH₃), and resuspended into LiAc/TE (2.5 ml).

[0373] Transformation took place by mixing the prepared cells (100 μl)with freshly denatured single stranded salmon testes DNA (LofstrandLabs, Gaithersburg, Md.) and transforming DNA (1 μg, vol.<10 μl) inmicrofuge tubes. The mixture was mixed briefly by vortexing, then 40%PEG/TE (600 μl, 40% polyethylene glycol-4000, 10 mM Tris-HCl, 1 mM EDTA,100 mM Li₂OOCCH₃, pH 7.5) was added. This mixture was gently mixed andincubated at 30° C. while agitating for 30 minutes. The cells were thenheat shocked at 42° C. for 15 minutes, and the reaction vesselcentrifuged in a microfuge at 12,000 rpm for 5-10 seconds, decanted andresuspended into TE (500 μl, 10 mM Tris-HCl, 1 mM EDTA pH 7.5) followedby recentrifugation. The cells were then diluted into TE (1 ml) andaliquots (200 μl) were spread onto the selective media previouslyprepared in 150 mm growth plates (VWR).

[0374] Alternatively, instead of multiple small reactions, thetransformation was performed using a single, large scale reaction,wherein reagent amounts were scaled up accordingly.

[0375] The selective media used was a synthetic complete dextrose agarlacking uracil (SCD-Ura) prepared as described in Kaiser et al., Methodsin Yeast Genetics, Cold Spring Harbor Press, Cold Spring Harbor, N.Y.,p. 208-210 (1994). Transformants were grown at 30° C. for 2-3 days.

[0376] The detection of colonies secreting amylase was performed byincluding red starch in the selective growth media. Starch was coupledto the red dye (Reactive Red-120, Sigma) as per the procedure describedby Biely et al., Anal. Biochem., 172:176-179 (1988). The coupled starchwas incorporated into the SCD-Ura agar plates at a final concentrationof 0.15% (w/v), and was buffered with potassium phosphate to a pH of 7.0(50-100 mM final concentration).

[0377] The positive colonies were picked and streaked across freshselective media (onto 150 mm plates) in order to obtain well isolatedand identifiable single colonies. Well isolated single colonies positivefor amylase secretion were detected by direct incorporation of redstarch into buffered SCD-Ura agar. Positive colonies were determined bytheir ability to break down starch resulting in a clear halo around thepositive colony visualized directly.

[0378] 4. Isolation of DNA by PCR Amplification

[0379] When a positive colony was isolated, a portion of it was pickedby a toothpick and diluted into sterile water (30 μl) in a 96 wellplate. At this time, the positive colonies were either frozen and storedfor subsequent analysis or immediately amplified. An aliquot of cells (5μl) was used as a template for the PCR reaction in a 25 μl volumecontaining: 0.5 μl Klentaq (Clontech, Palo Alto, Calif.); 4.0 μl 10 mMdNTP's (Perkin Elmer-Cetus); 2.5 μl Kentaq buffer (Clontech); 0.25 μlforward oligo 1; 0.25 μl reverse oligo 2; 12.5 μl distilled water. Thesequence of the forward oligonucleotide 1 was:

[0380] 5′-TGTAAAACGACGGCCAGTTAAATAGACCTGCAATTATTAATCT-3′ (SEQ ID NO:115)

[0381] The sequence of reverse oligonucleotide 2 was:

[0382] 5′-CAGGAAACAGCTATGACCACCTGCACACCTGCAAATCCATT-3′ (SEQ ID NO:116)

[0383] PCR was then performed as follows: a. Denature 92° C.,  5 minutesb.  3 cycles of: Denature 92° C., 30 seconds Anneal 59° C., 30 secondsExtend 72° C., 60 seconds c.  3 cycles of: Denature 92° C., 30 secondsAnneal 57° C., 30 seconds Extend 72° C., 60 seconds d. 25 cycles of:Denature 92° C., 30 seconds Anneal 55° C., 30 seconds Extend 72° C., 60seconds e. Hold  4° C.

[0384] The underlined regions of the oligonucleotides annealed to theADH promoter region and the amylase region, respectively, and amplifieda 307 bp region from vector pSST-AMY.0 when no insert was present.Typically, the first 18 nucleotides of the 5′ end of theseoligonucleotides contained annealing sites for the sequencing primers.Thus, the total product of the PCR reaction from an empty vector was 343bp. However, signal sequence-fused cDNA resulted in considerably longernucleotide sequences.

[0385] Following the PCR, an aliquot of the reaction (5 μl) was examinedby agarose gel electrophoresis in a 1% agarose gel using aTris-Borate-EDTA (TBE) buffering system as described by Sambrook et al.,supra. Clones resulting in a single strong PCR product larger than 400bp were further analyzed by DNA sequencing after purification with a 96Qiaquick PCR clean-up column (Qiagen Inc., Chatsworth, Calif.).

Example 3 Isolation of cDNA Clones Using Signal Algorithm Analysis

[0386] Various polypeptide-encoding nucleic acid sequences wereidentified by applying a proprietary signal sequence finding algorithmdeveloped by Genentech, Inc. (South San Francisco, Calif.) upon ESTs aswell as clustered and assembled EST fragments from public (e.g.,GenBank) and/or private (LIFESEQ®, Incyte Pharmaceuticals, Inc., PaloAlto, Calif.) databases. The signal sequence algorithm computes asecretion signal score based on the character of the DNA nucleotidessurrounding the first and optionally the second methionine codon(s)(ATG) at the 5′-end of the sequence or sequence fragment underconsideration. The nucleotides following the first ATG must code for atleast 35 unambiguous amino acids without any stop codons. If the firstATG has the required amino acids, the second is not examined. If neithermeets the requirement, the candidate sequence is not scored. In order todetermine whether the EST sequence contains an authentic signalsequence, the DNA and corresponding amino acid sequences surrounding theATG codon are scored using a set of seven sensors (evaluationparameters) known to be associated with secretion signals. Use of thisalgorithm resulted in the identification of numerouspolypeptide-encoding nucleic acid sequences.

Example 4 Isolation of cDNA Clones Encoding Human PRO Polypeptides

[0387] Using the techniques described in Examples 1 to 3 above, numerousfull-length cDNA clones were identified as encoding PRO polypeptides asdisclosed herein. These cDNAs were then deposited under the terms of theBudapest Treaty with the American Type Culture Collection, 10801University Blvd., Manassas, Va. 20110-2209, USA (ATCC) as shown in Table7 below. TABLE 7 Material ATCC Dep. No. Deposit Date DNA16422-1209209929 Jun. 2, 1998 DNA19902-1669 203454 Nov. 3, 1998 DNA21624-1391209917 Jun. 2, 1998 DNA34387-1138 209260 Sep. 16, 1997 DNA35880-1160209379 Oct. 16, 1997 DNA39984-1221 209435 Nov. 7, 1997 DNA44189-1322209699 Mar. 26, 1998 DNA48303-2829 PTA-1342 Feb. 8, 2000 DNA48320-1433209904 May 27, 1998 DNA56049-2543 203662 Feb. 9, 1999 DNA57694-1341203017 Jun. 23, 1998 DNA59208-1373 209881 May 20, 1998 DNA59214-1449203046 Jul. 1, 1998 DNA59485-1336 203015 Jun. 23, 1998 DNA64966-1575203575 Jan. 12, 1999 DNA82403-2959 PTA-2317 Aug. 1, 2000 DNA83505-2606PTA-132 May 25, 1999 DNA84927-2585 203865 Mar. 23, 1999 DNA92264-2616203969 Apr. 27, 1999 DNA94713-2561 203835 Mar. 9, 1999 DNA96869-2673PTA-255 Jun. 22, 1999 DNA96881-2699 PTA-553 Aug. 17, 1999 DNA96889-2641PTA-119 May 25, 1999 DNA96898-2640 PTA-122 May 25, 1999 DNA97003-2649PTA-43 May 11, 1999 DNA98565-2701 PTA-481 Aug. 3, 1999 DNA102846-2742PTA-545 Aug. 17, 1999 DNA102847-2726 PTA-517 Aug. 10, 1999DNA102880-2689 PTA-383 Jul. 20, 1999 DNA105782-2683 PTA-387 Jul. 20,1999 DNA108912-2680 PTA-124 May, 25, 1999 DNA115253-2757 PTA-612 Aug.31, 1999 DNA119302-2737 PTA-520 Aug. 10, 1999 DNA119536-2752 PTA-551Aug. 17, 1999 DNA119542-2754 PTA-619 Aug. 31, 1999 DNA143498-2824PTA-1263 Feb. 2, 2000 DNA145583-2820 PTA-1179 Jan. 11, 2000DNA161000-2896 PTA-1731 Apr. 18, 2000 DNA161005-2943 PTA-2243 Jun. 27,2000 DNA170245-3053 PTA-2952 Jan. 23, 2001 DNA171771-2919 PTA-1902 May23, 2000 DNA173157-2981 PTA-2388 Aug. 8, 2000 DNA175734-2985 PTA-2455Sep. 12, 2000 DNA176108-3040 PTA-2824 Dec. 19, 2000 DNA190710-3028PTA-2822 Dec. 19, 2000 DNA190803-3019 PTA-2785 Dec. 12, 2000DNA191064-3069 PTA-3016 Feb. 6, 2001 DNA194909-3013 PTA-2779 Dec. 12,2000 DNA203532-3029 PTA-2823 Dec. 19, 2000 DNA213858-3060 PTA-2958 Jan.23, 2001 DNA216676-3083 PTA-3157 Mar. 6, 2001 DNA222653-3104 PTA-3330Apr. 24, 2001 DNA96897-2688 PTA-379 Jul. 20, 1999 DNA142917-3081PTA-3155 Mar. 6, 2001 DNA142930-2914 PTA-1901 May 23, 2000DNA147253-2983 PTA-2405 Aug. 22, 2000 DNA149927-2887 PTA-1782 Apr. 25,2000

[0388] These deposits were made under the provisions of the BudapestTreaty on the International Recognition of the Deposit of Microorganismsfor the Purpose of Patent Procedure and the Regulations thereunder(Budapest Treaty). This assures maintenance of a viable culture of thedeposit for 30 years from the date of deposit. The deposits will be madeavailable by ATCC under the terms of the Budapest Treaty, and subject toan agreement between Genentech, Inc. and ATCC, which assures permanentand unrestricted availability of the progeny of the culture of thedeposit to the public upon issuance of the pertinent U.S. patent or uponlaying open to the public of any U.S. or foreign patent application,whichever comes first, and assures availability of the progeny to onedetermined by the U.S. Commissioner of Patents and Trademarks to beentitled thereto according to 35 USC § 122 and the Commissioner's rulespursuant thereto (including 37 CFR § 1.14 with particular reference to886 OG 638).

[0389] The assignee of the present application has agreed that if aculture of the materials on deposit should die or be lost or destroyedwhen cultivated under suitable conditions, the materials will bepromptly replaced on notification with another of the same. Availabilityof the deposited material is not to be construed as a license topractice the invention in contravention of the rights granted under theauthority of any government in accordance with its patent laws.

EXAMPLE 5 Use of PRO as a Hybridization Probe

[0390] The following method describes use of a nucleotide sequenceencoding PRO as a hybridization probe.

[0391] DNA comprising the coding sequence of full-length or mature PROas disclosed herein is employed as a probe to screen for homologous DNAs(such as those encoding naturally-occurring variants of PRO) in humantissue cDNA libraries or human tissue genomic libraries.

[0392] Hybridization and washing of filters containing either libraryDNAs is performed under the following high stringency conditions.Hybridization of radiolabeled PRO-derived probe to the filters isperformed in a solution of 50% formamide, 5×SSC, 0.1% SDS, 0.1% sodiumpyrophosphate, 50 mM sodium phosphate, pH 6.8, 2×Denhardt's solution,and 10% dextran sulfate at 42° C. for 20 hours. Washing of the filtersis performed in an aqueous solution of 0.1×SSC and 0.1% SDS at 42° C.

[0393] DNAs having a desired sequence identity with the DNA encodingfull-length native sequence PRO can then be identified using standardtechniques known in the art.

Example 6 Expression of PRO in E. coli

[0394] This example illustrates preparation of an unglycosylated form ofPRO by recombinant expression in E. coli.

[0395] The DNA sequence encoding PRO is initially amplified usingselected PCR primers. The primers should contain restriction enzymesites which correspond to the restriction enzyme sites on the selectedexpression vector. A variety of expression vectors may be employed. Anexample of a suitable vector is pBR322 (derived from E. coli; seeBolivar et al., Gene, 2:95 (1977)) which contains genes for ampicillinand tetracycline resistance. The vector is digested with restrictionenzyme and dephosphorylated. The PCR amplified sequences are thenligated into the vector. The vector will preferably include sequenceswhich encode for an antibiotic resistance gene, a trp promoter, apolyhis leader (including the first six STII codons, polyhis sequence,and enterokinase cleavage site), the PRO coding region, lambdatranscriptional terminator, and an argU gene.

[0396] The ligation mixture is then used to transform a selected E. colistrain using the methods described in Sambrook et al., supra.Transformants are identified by their ability to grow on LB plates andantibiotic resistant colonies are then selected. Plasmid DNA can beisolated and confirmed by restriction analysis and DNA sequencing.

[0397] Selected clones can be grown overnight in liquid culture mediumsuch as LB broth supplemented with antibiotics. The overnight culturemay subsequently be used to inoculate a larger scale culture. The cellsare then grown to a desired optical density, during which the expressionpromoter is turned on.

[0398] After culturing the cells for several more hours, the cells canbe harvested by centrifugation. The cell pellet obtained by thecentrifugation can be solubilized using various agents known in the art,and the solubilized PRO protein can then be purified using a metalchelating column under conditions that allow tight binding of theprotein.

[0399] PRO may be expressed in E. coli in a poly-His tagged form, usingthe following procedure. The DNA encoding PRO is initially amplifiedusing selected PCR primers. The primers will contain restriction enzymesites which correspond to the restriction enzyme sites on the selectedexpression vector, and other useful sequences providing for efficientand reliable translation initiation, rapid purification on a metalchelation column, and proteolytic removal with enterokinase. ThePCR-amplified, poly-His tagged sequences are then ligated into anexpression vector, which is used to transform an E. coli host based onstrain 52 (W3110 fuhA(tonA) lon galE rpoHts(htpRts) clpP(lacIq).Transformants are first grown in LB containing 50 mg/ml carbenicillin at30° C. with shaking until an O.D.600 of 3-5 is reached. Cultures arethen diluted 50-100 fold into CRAP media (prepared by mixing 3.57 g(NH₄)₂SO₄, 0.71 g sodium citrate.2H2O, 1.07 g KCl, 5.36 g Difco yeastextract, 5.36 g Sheffield hycase SF in 500 mL water, as well as 110 mMMPOS, pH 7.3, 0.55% (w/v) glucose and 7 mM MgSO₄) and grown forapproximately 20-30 hours at 30° C. with shaking. Samples are removed toverify expression by SDS-PAGE analysis, and the bulk culture iscentrifuged to pellet the cells. Cell pellets are frozen untilpurification and refolding.

[0400]E. coli paste from 0.5 to 1 L fermentations (6-10 g pellets) isresuspended in 10 volumes (w/v) in 7 M guanidine, 20 mM Tris, pH 8buffer. Solid sodium sulfite and sodium tetrathionate is added to makefinal concentrations of 0.1M and 0.02 M, respectively, and the solutionis stirred overnight at 4° C. This step results in a denatured proteinwith all cysteine residues blocked by sulfitolization. The solution iscentrifuged at 40,000 rpm in a Beckman Ultracentifuge for 30 min. Thesupernatant is diluted with 3-5 volumes of metal chelate column buffer(6 M guanidine, 20 mM Tris, pH 7.4) and filtered through 0.22 micronfilters to clarify. The clarified extract is loaded onto a 5 ml QiagenNi-NTA metal chelate column equilibrated in the metal chelate columnbuffer. The column is washed with additional buffer containing 50 mMimidazole (Calbiochem, Utrol grade), pH 7.4. The protein is eluted withbuffer containing 250 mM imidazole. Fractions containing the desiredprotein are pooled and stored at 4° C. Protein concentration isestimated by its absorbance at 280 nm using the calculated extinctioncoefficient based on its amino acid sequence.

[0401] The proteins are refolded by diluting the sample slowly intofreshly prepared refolding buffer consisting of: 20 mM Tris, pH 8.6, 0.3M NaCl, 2.5 M urea, 5 mM cysteine, 20 mM glycine and 1 mM EDTA.Refolding volumes are chosen so that the final protein concentration isbetween 50 to 100 micrograms/ml. The refolding solution is stirredgently at 4° C. for 12-36 hours. The refolding reaction is quenched bythe addition of TFA to a final concentration of 0.4% (pH ofapproximately 3). Before further purification of the protein, thesolution is filtered through a 0.22 micron filter and acetonitrile isadded to 2-10% final concentration. The refolded protein ischromatographed on a Poros R1/H reversed phase column using a mobilebuffer of 0.1% TFA with elution with a gradient of acetonitrile from 10to 80%. Aliquots of fractions with A280 absorbance are analyzed on SDSpolyacrylamide gels and fractions containing homogeneous refoldedprotein are pooled. Generally, the properly refolded species of mostproteins are eluted at the lowest concentrations of acetonitrile sincethose species are the most compact with their hydrophobic interiorsshielded from interaction with the reversed phase resin. Aggregatedspecies are usually eluted at higher acetonitrile concentrations. Inaddition to resolving misfolded forms of proteins from the desired form,the reversed phase step also removes endotoxin from the samples.

[0402] Fractions containing the desired folded PRO polypeptide arepooled and the acetonitrile removed using a gentle stream of nitrogendirected at the solution. Proteins are formulated into 20 mM Hepes, pH6.8 with 0.14 M sodium chloride and 4% mannitol by dialysis or by gelfiltration using G25 Superfine (Pharmacia) resins equilibrated in theformulation buffer and sterile filtered.

[0403] Many of the PRO polypeptides disclosed herein were successfullyexpressed as described above.

Example 7 Expression of PRO in Mammalian Cells

[0404] This example illustrates preparation of a potentiallyglycosylated form of PRO by recombinant expression in mammalian cells.

[0405] The vector, pRK5 (see EP 307,247, published Mar. 15, 1989), isemployed as the expression vector. Optionally, the PRO DNA is ligatedinto pRK5 with selected restriction enzymes to allow insertion of thePRO DNA using ligation methods such as described in Sambrook et al.,supra. The resulting vector is called pRK5-PRO.

[0406] In one embodiment, the selected host cells may be 293 cells.Human 293 cells (ATCC CCL 1573) are grown to confluence in tissueculture plates in medium such as DMEM supplemented with fetal calf serumand optionally, nutrient components and/or antibiotics. About 10 μgpRK5-PRO DNA is mixed with about 1 μg DNA encoding the VA RNA gene[Thimmappaya et al., Cell, 31:543 (1982)] and dissolved in 500 μl of 1mM Tris-HCl, 0.1 mM EDTA, 0.227 M CaCl₂. To this mixture is added,dropwise, 500 μl of 50 mM HEPES (pH 7.35), 280 mM NaCl, 1.5 mM NaPO₄,and a precipitate is allowed to form for 10 minutes at 25° C. Theprecipitate is suspended and added to the 293 cells and allowed tosettle for about four hours at 37° C. The culture medium is aspiratedoff and 2 ml of 20% glycerol in PBS is added for 30 seconds. The 293cells are then washed with serum free medium, fresh medium is added andthe cells are incubated for about 5 days.

[0407] Approximately 24 hours after the transfections, the culturemedium is removed and replaced with culture medium (alone) or culturemedium containing 200 μCi/ml ³⁵S-cysteine and 200 μCi/ml ³⁵S-methionine.After a 12 hour incubation, the conditioned medium is collected,concentrated on a spin filter, and loaded onto a 15% SDS gel. Theprocessed gel may be dried and exposed to film for a selected period oftime to reveal the presence of PRO polypeptide. The cultures containingtransfected cells may undergo further incubation (in serum free medium)and the medium is tested in selected bioassays.

[0408] In an alternative technique, PRO may be introduced into 293 cellstransiently using the dextran sulfate method described by Somparyrac etal., Proc. Natl. Acad. Sci., 12:7575 (1981). 293 cells are grown tomaximal density in a spinner flask and 700 μg pRK5-PRO DNA is added. Thecells are first concentrated from the spinner flask by centrifugationand washed with PBS. The DNA-dextran precipitate is incubated on thecell pellet for four hours. The cells are treated with 20% glycerol for90 seconds, washed with tissue culture medium, and re-introduced intothe spinner flask containing tissue culture medium, 5 μg/ml bovineinsulin and 0.1 μg/ml bovine transferrin. After about four days, theconditioned media is centrifuged and filtered to remove cells anddebris. The sample containing expressed PRO can then be concentrated andpurified by any selected method, such as dialysis and/or columnchromatography.

[0409] In another embodiment, PRO can be expressed in CHO cells. ThepRK5-PRO can be transfected into CHO cells using known reagents such asCaPO₄ or DEAE-dextran. As described above, the cell cultures can beincubated, and the medium replaced with culture medium (alone) or mediumcontaining a radiolabel such as ³⁵S-methione. After determining thepresence of PRO polypeptide, the culture medium may be replaced withserum free medium. Preferably, the cultures are incubated for about 6days, and then the conditioned medium is harvested. The mediumcontaining the expressed PRO can then be concentrated and purified byany selected method.

[0410] Epitope-tagged PRO may also be expressed in host CHO cells. ThePRO may be subcloned out of the pRK5 vector. The subclone insert canundergo PCR to fuse in frame with a selected epitope tag such as apoly-his tag into a Baculovirus expression vector. The poly-his taggedPRO insert can then be subcloned into a SV40 driven vector containing aselection marker such as DHFR for selection of stable clones. Finally,the CHO cells can be transfected (as described above) with the SV40driven vector. Labeling may be performed, as described above, to verifyexpression. The culture medium containing the expressed poly-His taggedPRO can then be concentrated and purified by any selected method, suchas by Ni²⁺-chelate affinity chromatography.

[0411] PRO may also be expressed in CHO and/or COS cells by a transientexpression procedure or in CHO cells by another stable expressionprocedure.

[0412] Stable expression in CHO cells is performed using the followingprocedure. The proteins are expressed as an IgG construct(immunoadhesin), in which the coding sequences for the soluble forms(e.g. extracellular domains) of the respective proteins are fused to anIgG1 constant region sequence containing the hinge, CH2 and CH2 domainsand/or is a poly-His tagged form.

[0413] Following PCR amplification, the respective DNAs are subcloned ina CHO expression vector using standard techniques as described inAusubel et al., Current Protocols of Molecular Biology, Unit 3.16, JohnWiley and Sons (1997). CHO expression vectors are constructed to havecompatible restriction sites 5′ and 3′ of the DNA of interest to allowthe convenient shuttling of cDNA's. The vector used expression in CHOcells is as described in Lucas et al., Nucl. Acids Res. 24:9 (1774-1779(1996), and uses the SV40 early promoter/enhancer to drive expression ofthe cDNA of interest and dihydrofolate reductase (DHFR). DHFR expressionpermits selection for stable maintenance of the plasmid followingtransfection.

[0414] Twelve micrograms of the desired plasmid DNA is introduced intoapproximately 10 million CHO cells using commercially availabletransfection reagents Superfect® (Qiagen), Dosper® or Fugene®(Boehringer Mannheim). The cells are grown as described in Lucas et al.,supra. Approximately 3×10⁷ cells are frozen in an ampule for furthergrowth and production as described below.

[0415] The ampules containing the plasmid DNA are thawed by placementinto water bath and mixed by vortexing. The contents are pipetted into acentrifuge tube containing 10 mLs of media and centrifuged at 1000 rpmfor 5 minutes. The supernatant is aspirated and the cells areresuspended in 10 mL of selective media (0.2 μm filtered PS20 with 5%0.2 μm diafiltered fetal bovine serum). The cells are then aliquotedinto a 100 mL spinner containing 90 mL of selective media. After 1-2days, the cells are transferred into a 250 mL spinner filled with 150 mLselective growth medium and incubated at 37° C. After another 2-3 days,250 mL, 500 mL and 200 mL spinners are seeded with 3×10⁵ cells/mL. Thecell media is exchanged with fresh media by centrifugation andresuspension in production medium. Although any suitable CHO media maybe employed, a production medium described in U.S. Pat. No. 5,122,469,issued Jun. 16, 1992 may actually be used. A 3L production spinner isseeded at 1.2×10⁶ cells/mL. On day 0, the cell number pH ie determined.On day 1, the spinner is sampled and sparging with filtered air iscommenced. On day 2, the spinner is sampled, the temperature shifted to33° C., and 30 mL of 500 g/L glucose and 0.6 mL of 10% antifoam (e.g.,35% polydimethylsiloxane emulsion, Dow Corning 365 Medical GradeEmulsion) taken. Throughout the production, the pH is adjusted asnecessary to keep it at around 7.2. After 10 days, or until theviability dropped below 70%, the cell culture is harvested bycentrifugation and filtering through a 0.22 μm filter. The filtrate waseither stored at 4° C. or immediately loaded onto columns forpurification.

[0416] For the poly-His tagged constructs, the proteins are purifiedusing a Ni-NTA column (Qiagen). Before purification, imidazole is addedto the conditioned media to a concentration of 5 mM. The conditionedmedia is pumped onto a 6 ml Ni-NTA column equilibrated in 20 mM Hepes,pH 7.4, buffer containing 0.3 M NaCl and 5 mM imidazole at a flow rateof 4-5 ml/min. at 4° C. After loading, the column is washed withadditional equilibration buffer and the protein eluted withequilibration buffer containing 0.25 M imidazole. The highly purifiedprotein is subsequently desalted into a storage buffer containing 10 mMHepes, 0.14 M NaCl and 4% mannitol, pH 6.8, with a 25 ml G25 Superfine(Pharmacia) column and stored at −80° C.

[0417] Immunoadhesin (Fc-containing) constructs are purified from theconditioned media as follows. The conditioned medium is pumped onto a 5ml Protein A column (Pharmacia) which had been equilibrated in 20 mM Naphosphate buffer, pH 6.8. After loading, the column is washedextensively with equilibration buffer before elution with 100 mM citricacid, pH 3.5. The eluted protein is immediately neutralized bycollecting 1 ml fractions into tubes containing 275 μL of 1 M Trisbuffer, pH 9. The highly purified protein is subsequently desalted intostorage buffer as described above for the poly-His tagged proteins. Thehomogeneity is assessed by SDS polyacrylamide gels and by N-terminalamino acid sequencing by Edman degradation.

[0418] Many of the PRO polypeptides disclosed herein were successfullyexpressed as described above.

Example 8 Expression of PRO in Yeast

[0419] The following method describes recombinant expression of PRO inyeast.

[0420] First, yeast expression vectors are constructed for intracellularproduction or secretion of PRO from the ADH2/GAPDH promoter. DNAencoding PRO and the promoter is inserted into suitable restrictionenzyme sites in the selected plasmid to direct intracellular expressionof PRO. For secretion, DNA encoding PRO can be cloned into the selectedplasmid, together with DNA encoding the ADH2/GAPDH promoter, a nativePRO signal peptide or other mammalian signal peptide, or, for example, ayeast alpha-factor or invertase secretory signal/leader sequence, andlinker sequences (if needed) for expression of PRO.

[0421] Yeast cells, such as yeast strain AB110, can then be transformedwith the expression plasmids described above and cultured in selectedfermentation media. The transformed yeast supernatants can be analyzedby precipitation with 10% trichloroacetic acid and separation bySDS-PAGE, followed by staining of the gels with Coomassie Blue stain.

[0422] Recombinant PRO can subsequently be isolated and purified byremoving the yeast cells from the fermentation medium by centrifugationand then concentrating the medium using selected cartridge filters. Theconcentrate containing PRO may further be purified using selected columnchromatography resins.

[0423] Many of the PRO polypeptides disclosed herein were successfullyexpressed as described above.

Example 9 Expression of PRO in Baculovirus-Infected Insect Cells

[0424] The following method describes recombinant expression of PRO inBaculovirus-infected Insect Cells

[0425] The sequence coding for PRO is fused upstream of an epitope tagcontained within a baculovirus expression vector. Such epitope tagsinclude poly-his tags and immunoglobulin tags (like Fc regions of IgG).A variety of plasmids may be employed, including plasmids derived fromcommercially available plasmids such as pV_(L)1393 (Novagen). Briefly,the sequence encoding PRO or the desired portion of the coding sequenceof PRO such as the sequence encoding the extracellular domain of atransmembrane protein or the sequence encoding the mature protein if theprotein is extracellular is amplified by PCR with primers complementaryto the 5′ and 3′ regions. The 5′ primer may incorporate flanking(selected) restriction enzyme sites. The product is then digested withthose selected restriction enzymes and subcloned into the expressionvector.

[0426] Recombinant baculovirus is generated by co-transfecting the aboveplasmid and BaculoGold™ virus DNA (Pharmingen) into Spodopterafrugiperda (“Sf9”) cells (ATCC CRL 1711) using lipofectin (commerciallyavailable from GIBCO-BRL). After 4-5 days of incubation at 28° C., thereleased viruses are harvested and used for further amplifications.Viral infection and protein expression are performed as described byO'Reilley et al., Baculovirus expression vectors: A Laboratory Manual,Oxford: Oxford University Press (1994).

[0427] Expressed poly-his tagged PRO can then be purified, for example,by Ni²⁺-chelate affinity chromatography as follows. Extracts areprepared from recombinant virus-infected Sf9 cells as described byRupert et al., Nature, 362:175-179 (1993). Briefly, Sf9 cells arewashed, resuspended in sonication buffer (25 mL Hepes, pH 7.9; 12.5 mMMgCl₂; 0.1 mM EDTA; 10% glycerol; 0.1% NP-40; 0.4 M KCl), and sonicatedtwice for 20 seconds on ice. The sonicates are cleared bycentrifugation, and the supernatant is diluted 50-fold in loading buffer(50 mM phosphate, 300 mM NaCl, 10% glycerol, pH 7.8) and filteredthrough a 0.45 μm filter. A Ni²⁺-NTA agarose column (commerciallyavailable from Qiagen) is prepared with a bed volume of 5 mL, washedwith 25 mL of water and equilibrated with 25 mL of loading buffer. Thefiltered cell extract is loaded onto the column at 0.5 mL per minute.The column is washed to baseline A₂₈₀ with loading buffer, at whichpoint fraction collection is started. Next, the column is washed with asecondary wash buffer (50 mM phosphate; 300 mM NaCl, 10% glycerol, pH6.0), which elutes nonspecifically bound protein. After reaching A₂₈₀baseline again, the column is developed with a 0 to 500 mM Imidazolegradient in the secondary wash buffer. One mL fractions are collectedand analyzed by SDS-PAGE and silver staining or Western blot withNi²⁺-NTA-conjugated to alkaline phosphatase (Qiagen). Fractionscontaining the eluted His₁₀-tagged PRO are pooled and dialyzed againstloading buffer.

[0428] Alternatively, purification of the IgG tagged (or Fc tagged) PROcan be performed using known chromatography techniques, including forinstance, Protein A or protein G column chromatography.

[0429] Many of the PRO polypeptides disclosed herein were successfullyexpressed as described above.

Example 10 Preparation of Antibodies that Bind PRO

[0430] This example illustrates preparation of monoclonal antibodieswhich can specifically bind PRO.

[0431] Techniques for producing the monoclonal antibodies are known inthe art and are described, for instance, in Goding, supra. Immunogensthat may be employed include purified PRO, fusion proteins containingPRO, and cells expressing recombinant PRO on the cell surface. Selectionof the immunogen can be made by the skilled artisan without undueexperimentation.

[0432] Mice, such as Balb/c, are immunized with the PRO immunogenemulsified in complete Freund's adjuvant and injected subcutaneously orintraperitoneally in an amount from 1-100 micrograms. Alternatively, theimmunogen is emulsified in MPL-TDM adjuvant (Ribi ImmunochemicalResearch, Hamilton, Mont.) and injected into the animal's hind footpads. The immunized mice are then boosted 10 to 12 days later withadditional immunogen emulsified in the selected adjuvant. Thereafter,for several weeks, the mice may also be boosted with additionalimmunization injections. Serum samples may be periodically obtained fromthe mice by retro-orbital bleeding for testing in ELISA assays to detectanti-PRO antibodies.

[0433] After a suitable antibody titer has been detected, the animals“positive” for antibodies can be injected with a final intravenousinjection of PRO. Three to four days later, the mice are sacrificed andthe spleen cells are harvested. The spleen cells are then fused (using35% polyethylene glycol) to a selected murine myeloma cell line such asP3X63AgU.1, available from ATCC, No. CRL 1597. The fusions generatehybridoma cells which can then be plated in 96 well tissue cultureplates containing HAT (hypoxanthine, aminopterin, and thymidine) mediumto inhibit proliferation of non-fused cells, myeloma hybrids, and spleencell hybrids.

[0434] The hybridoma cells will be screened in an ELISA for reactivityagainst PRO. Determination of “positive” hybridoma cells secreting thedesired monoclonal antibodies against PRO is within the skill in theart.

[0435] The positive hybridoma cells can be injected intraperitoneallyinto syngeneic Balb/c mice to produce ascites containing the anti-PROmonoclonal antibodies. Alternatively, the hybridoma cells can be grownin tissue culture flasks or roller bottles. Purification of themonoclonal antibodies produced in the ascites can be accomplished usingammonium sulfate precipitation, followed by gel exclusionchromatography. Alternatively, affinity chromatography based uponbinding of antibody to protein A or protein G can be employed.

Example 11 Purification of PRO Polypeptides Using Specific Antibodies

[0436] Native or recombinant PRO polypeptides may be purified by avariety of standard techniques in the art of protein purification. Forexample, pro-PRO polypeptide, mature PRO polypeptide, or pre-PROpolypeptide is purified by immunoaffinity chromatography usingantibodies specific for the PRO polypeptide of interest. In general, animmunoaffinity column is constructed by covalently coupling the anti-PROpolypeptide antibody to an activated chromatographic resin.

[0437] Polyclonal immunoglobulins are prepared from immune sera eitherby precipitation with ammonium sulfate or by purification on immobilizedProtein A (Pharmacia LKB Biotechnology, Piscataway, N.J.). Likewise,monoclonal antibodies are prepared from mouse ascites fluid by ammoniumsulfate precipitation or chromatography on immobilized Protein A.Partially purified immunoglobulin is covalently attached to achromatographic resin such as CnBr-activated SEPHAROSE™ (Pharmacia LKBBiotechnology). The antibody is coupled to the resin, the resin isblocked, and the derivative resin is washed according to themanufacturer's instructions.

[0438] Such an immunoaffinity column is utilized in the purification ofPRO polypeptide by preparing a fraction from cells containing PROpolypeptide in a soluble form. This preparation is derived bysolubilization of the whole cell or of a subcellular fraction obtainedvia differential centrifugation by the addition of detergent or by othermethods well known in the art. Alternatively, soluble PRO polypeptidecontaining a signal sequence may be secreted in useful quantity into themedium in which the cells are grown.

[0439] A soluble PRO polypeptide-containing preparation is passed overthe immunoaffinity column, and the column is washed under conditionsthat allow the preferential absorbance of PRO polypeptide (e.g., highionic strength buffers in the presence of detergent). Then, the columnis eluted under conditions that disrupt antibody/PRO polypeptide binding(e.g., a low pH buffer such as approximately pH 2-3, or a highconcentration of a chaotrope such as urea or thiocyanate ion), and PROpolypeptide is collected.

Example 12 Drug Screening

[0440] This invention is particularly useful for screening compounds byusing PRO polypeptides or binding fragment thereof in any of a varietyof drug screening techniques. The PRO polypeptide or fragment employedin such a test may either be free in solution, affixed to a solidsupport, borne on a cell surface, or located intracellularly. One methodof drug screening utilizes eukaryotic or prokaryotic host cells whichare stably transformed with recombinant nucleic acids expressing the PROpolypeptide or fragment. Drugs are screened against such transformedcells in competitive binding assays. Such cells, either in viable orfixed form, can be used for standard binding assays. One may measure,for example, the formation of complexes between PRO polypeptide or afragment and the agent being tested. Alternatively, one can examine thediminution in complex formation between the PRO polypeptide and itstarget cell or target receptors caused by the agent being tested.

[0441] Thus, the present invention provides methods of screening fordrugs or any other agents which can affect a PRO polypeptide-associateddisease or disorder. These methods comprise contacting such an agentwith an PRO polypeptide or fragment thereof and assaying (I) for thepresence of a complex between the agent and the PRO polypeptide orfragment, or (ii) for the presence of a complex between the PROpolypeptide or fragment and the cell, by methods well known in the art.In such competitive binding assays, the PRO polypeptide or fragment istypically labeled. After suitable incubation, free PRO polypeptide orfragment is separated from that present in bound form, and the amount offree or uncomplexed label is a measure of the ability of the particularagent to bind to PRO polypeptide or to interfere with the PROpolypeptide/cell complex.

[0442] Another technique for drug screening provides high throughputscreening for compounds having suitable binding affinity to apolypeptide and is described in detail in WO 84/03564, published on Sep.13, 1984. Briefly stated, large numbers of different small peptide testcompounds are synthesized on a solid substrate, such as plastic pins orsome other surface. As applied to a PRO polypeptide, the peptide testcompounds are reacted with PRO polypeptide and washed. Bound PROpolypeptide is detected by methods well known in the art. Purified PROpolypeptide can also be coated directly onto plates for use in theaforementioned drug screening techniques. In addition, non-neutralizingantibodies can be used to capture the peptide and immobilize it on thesolid support.

[0443] This invention also contemplates the use of competitive drugscreening assays in which neutralizing antibodies capable of binding PROpolypeptide specifically compete with a test compound for binding to PROpolypeptide or fragments thereof. In this manner, the antibodies can beused to detect the presence of any peptide which shares one or moreantigenic determinants with PRO polypeptide.

Example 13 Rational Drug Design

[0444] The goal of rational drug design is to produce structural analogsof biologically active polypeptide of interest (i.e., a PRO polypeptide)or of small molecules with which they interact, e.g., agonists,antagonists, or inhibitors. Any of these examples can be used to fashiondrugs which are more active or stable forms of the PRO polypeptide orwhich enhance or interfere with the function of the PRO polypeptide invivo (cf., Hodgson, Bio/Technology 9: 19-21 (1991)).

[0445] In one approach, the three-dimensional structure of the PROpolypeptide, or of an PRO polypeptide-inhibitor complex, is determinedby x-ray crystallography, by computer modeling or, most typically, by acombination of the two approaches. Both the shape and charges of the PROpolypeptide must be ascertained to elucidate the structure and todetermine active site(s) of the molecule. Less often, useful informationregarding the structure of the PRO polypeptide may be gained by modelingbased on the structure of homologous proteins. In both cases, relevantstructural information is used to design analogous PRO polypeptide-likemolecules or to identify efficient inhibitors. Useful examples ofrational drug design may include molecules which have improved activityor stability as shown by Braxton and Wells, Biochemistry, 31:7796-7801(1992) or which act as inhibitors, agonists, or antagonists of nativepeptides as shown by Athauda et al., J. Biochem., 113:742-746 (1993).

[0446] It is also possible to isolate a target-specific antibody,selected by functional assay, as described above, and then to solve itscrystal structure. This approach, in principle, yields a pharmacore uponwhich subsequent drug design can be based. It is possible to bypassprotein crystallography altogether by generating anti-idiotypicantibodies (anti-ids) to a functional, pharmacologically activeantibody. As a mirror image of a mirror image, the binding site of theanti-ids would be expected to be an analog of the original receptor. Theanti-id could then be used to identify and isolate peptides from banksof chemically or biologically produced peptides. The isolated peptideswould then act as the pharmacore.

[0447] By virtue of the present invention, sufficient amounts of the PROpolypeptide may be made available to perform such analytical studies asX-ray crystallography. In addition, knowledge of the PRO polypeptideamino acid sequence provided herein will provide guidance to thoseemploying computer modeling techniques in place of or in addition tox-ray crystallography.

Example 14 Ability of PRO Polypeptides to Stimulate the Release ofProteoglycans from Cartilage (Assay 97)

[0448] The ability of various PRO polypeptides to stimulate the releaseof proteoglycans from cartilage tissue was tested as follows.

[0449] The metacarphophalangeal joint of 4-6 month old pigs wasaseptically dissected, and articular cartilage was removed by free handslicing being careful to avoid the underlying bone. The cartilage wasminced and cultured in bulk for 24 hours in a humidified atmosphere of95% air, 5% CO₂ in serum free (SF) media (DME/F12 1:1) with 0.1% BSA and100 μg/ml penicillin and 100 ug/ml streptomycin. After washing threetimes, approximately 100 mg of articular cartilage was aliquoted intomicronics tubes and incubated for an additional 24 hours in the above SFmedia. PRO polypeptides were then added at 1% either alone or incombination with 18 ng/ml interleukin-1α, a known stimulator ofproteoglycan release from cartilage tissue. The supernatant was thenharvested and assayed for the amount of proteoglycans using the1,9-dimethyl-methylene blue (DMB) colorimetric assay (Farndale andButtle, Biochem. Biophys. Acta 883:173-177 (1985)). A positive result inthis assay indicates that the test polypeptide will find use, forexample, in the treatment of sports-related joint problems, articularcartilage defects, osteoarthritis or rheumatoid arthritis.

[0450] When various PRO polypeptides were tested in the above assay, thepolypeptides demonstrated a marked ability to stimulate release ofproteoglycans from cartilage tissue both basally and after stimulationwith interleukin-1α and at 24 and 72 hours after treatment, therebyindicating that these PRO polypeptides are useful for stimulatingproteoglycan release from cartilage tissue. As such, these PROpolypeptides are useful for the treatment of sports-related jointproblems, articular cartilage defects, osteoarthritis or rheumatoidarthritis. PRO6018 polypeptide testing positive in this assay.

Example 15 Human Microvascular Endothelial Cell Proliferation (Assay146)

[0451] This assay is designed to determine whether PRO polypeptides ofthe present invention show the ability to induce proliferation of humanmicrovascular endothelial cells in culture and, therefore, function asuseful growth factors.

[0452] On day 0, human microvascular endothelial cells were plated in96-well plates at 1000 cells/well per 100 microliter and incubatedovernight in complete media [EBM-2 growth media, plus supplements:IGF-1; ascorbic acid; VEGF; hEGF; hFGF; hydrocortisone, gentamicin(GA-1000), and fetal bovine serum (FBS, Clonetics)]. On day 1, completemedia was replaced by basal media [EBM-2 plus 1% FBS] and addition ofPRO polypeptides at 1%, 0.1% and 0.01%. On day 7, an assessment of cellproliferation was performed using the ViaLight HS kit [ATP/luciferaseLumitech]. Results are expressed as % of the cell growth observed withcontrol buffer.

[0453] The following PRO polypeptides stimulated human microvascularendothelial cell proliferation in this assay: PRO1313, PRO20080, andPRO21383.

[0454] The following PRO polypeptides inhibited human microvascularendothelial cell proliferation in this assay: PRO6071, PRO4487, andPRO6006.

Example 16 Microarray Analysis to Detect Overexpression of PROPolypeptides in Cancerous Tumors

[0455] Nucleic acid microarrays, often containing thousands of genesequences, are useful for identifying differentially expressed genes indiseased tissues as compared to their normal counterparts. Using nucleicacid microarrays, test and control mRNA samples from test and controltissue samples are reverse transcribed and labeled to generate cDNAprobes. The cDNA probes are then hybridized to an array of nucleic acidsimmobilized on a solid support. The array is configured such that thesequence and position of each member of the array is known. For example,a selection of genes known to be expressed in certain disease states maybe arrayed on a solid support. Hybridization of a labeled probe with aparticular array member indicates that the sample from which the probewas derived expresses that gene. If the hybridization signal of a probefrom a test (disease tissue) sample is greater than hybridization signalof a probe from a control (normal tissue) sample, the gene or genesoverexpressed in the disease tissue are identified. The implication ofthis result is that an overexpressed protein in a diseased tissue isuseful not only as a diagnostic marker for the presence of the diseasecondition, but also as a therapeutic target for treatment of the diseasecondition.

[0456] The methodology of hybridization of nucleic acids and microarraytechnology is well known in the art. In the present example, thespecific preparation of nucleic acids for hybridization and probes,slides, and hybridization conditions are all detailed in U.S.Provisional Patent Application Serial No. 60/193,767, filed on Mar. 31,2000 and which is herein incorporated by reference.

[0457] In the present example, cancerous tumors derived from varioushuman tissues were studied for PRO polypeptide-encoding gene expressionrelative to non-cancerous human tissue in an attempt to identify thosePRO polypeptides which are overexpressed in cancerous tumors. Canceroushuman tumor tissue from any of a variety of different human tumors wasobtained and compared to a “universal” epithelial control sample whichwas prepared by pooling non-cancerous human tissues of epithelialorigin, including liver, kidney, and lung. mRNA isolated from the pooledtissues represents a mixture of expressed gene products from thesedifferent tissues. Microarray hybridization experiments using the pooledcontrol samples generated a linear plot in a 2-color analysis. The slopeof the line generated in a 2-color analysis was then used to normalizethe ratios of (test:control detection) within each experiment. Thenormalized ratios from various experiments were then compared and usedto identify clustering of gene expression. Thus, the pooled “universalcontrol” sample not only allowed effective relative gene expressiondeterminations in a simple 2-sample comparison, it also allowedmulti-sample comparisons across several experiments.

[0458] In the present experiments, nucleic acid probes derived from theherein described PRO polypeptide-encoding nucleic acid sequences wereused in the creation of the microarray and RNA from a panel of ninedifferent tumor tissues (listed below) were used for the hybridizationthereto. A value based upon the normalized ratio:experimental ratio wasdesignated as a “cutoff ratio”. Only values that were above this cutoffratio were determined to be significant. Table 8 below shows the resultsof these experiments, demonstrating that various PRO polypeptides of thepresent invention are significantly overexpressed in various human tumortissues, as compared to a non-cancerous human tissue control or otherhuman tumor tissues. As described above, these data demonstrate that thePRO polypeptides of the present invention are useful not only asdiagnostic markers for the presence of one or more cancerous tumors, butalso serve as therapeutic targets for the treatment of those tumors.TABLE 8 Molecule is overexpressed in: as compared to normal control:PRO240 breast tumor universal normal control PRO240 lung tumor universalnormal control PRO256 colon tumor universal normal control PRO256 lungtumor universal normal control PRO256 breast tumor universal normalcontrol PRO306 colon tumor universal normal control PRO306 lung tumoruniversal normal control PRO540 lung tumor urnversal normal controlPRO540 colon tumor universal normal control PRO773 breast tumoruniversal normal control PRO773 colon tumor universal normal controlPRO698 colon tumor universal normal control PRO698 breast tumoruniversal normal control PRO698 lung tumor universal normal controlPRO698 prostate tumor universal normal control PRO698 rectal minoruniversal normal control PRO3567 colon tumor universal normal controlPRO3567 breast tumor universal normal control PRO3567 lung tumoruniversal normal control PRO826 colon tumor universal normal controlPRO826 lung tumor universal normal control PRO826 breast tumor universalnormal control PRO826 rectal tumor universal normal control PRO826 livertumor universal normal control PRO1002 colon tumor universal normalcontrol PRO1002 lung tumor universal normal control PRO1068 colon tumoruniversal normal control PRO1068 breast tumor universal normal controlPRO1030 colon tumor universal normal control PRO1030 breast tumoruniversal normal control PRO1030 lung tumor universal normal controlPRO1030 prostate tumor universal normal control PRO1030 rectal tumoruniversal normal control PRO4397 colon tumor universal normal controlPRO4397 breast tumor universal normal control PRO4344 colon tumoruniversal normal control PRO4344 lung tumor universal normal controlPRO4344 rectal tumor universal normal control PRO4407 colon tumoruniversal normal control PRO4407 breast tumor universal normal controlPRO4407 lung tumor universal normal control PRO4407 liver tumoruniversal normal control PRO4407 rectal tumor universal normal controlPRO4316 colon tumor universal normal control PRO4316 prostate tumoruniversal normal control PRO5775 colon tumor universal normal controlPRO6016 colon tumor universal normal control PRO4980 breast tumoruniversal normal control PRO4980 colon tumor universal normal controlPRO4980 lung tumor universal normal control PRO6018 colon tumoruniversal normal control PRO7168 colon tumor universal normal controlPRO6000 colon tumor universal normal control PRO6006 colon tumoruniversal normal control PRO5800 colon tumor universal normal controlPRO5800 breast tumor universal normal control PRO5800 lung tumoruniversal normal control PRO5800 rectal tumor universal normal controlPRO7476 colon tumor universal normal control PRO10268 colon tumoruniversal normal control PRO6496 colon tumor universal normal controlPRO6496 breast tumor universal normal control PRO6496 lung tumoruniversal normal control PRO7422 colon tumor universal normal controlPRO7431 colon tumor universal normal control PRO28633 colon tumoruniversal normal control PRO28633 lung tumor universal normal controlPRO28633 liver tumor universal normal control PRO21485 colon tumoruniversal normal control PRO28700 breast tumor universal normal controlPRO28700 lung tumor universal normal control PRO28700 colon tumoruniversal normal control PRO34012 colon tumor universal normal controlPRO34012 lung tumor universal normal control PRO34003 colon tumoruniversal normal control PRO34003 lung tumor universal normal controlPRO34001 colon tumor universal normal control PRO34009 colon tumoruniversal normal control PRO34009 breast tumor universal normal controlPRO34009 lung tumor universal normal control PRO34009 rectal tumoruniversal normal control PRO34192 colon tumor universal normal controlPRO34564 colon tumor universal normal control PRO35444 colon tumoruniversal normal control PRO5998 colon tumor universal normal controlPRO5998 lung tumor universal normal control PRO5998 kidney tumoruniversal normal control PRO19651 colon tumor universal normal controlPRO20221 liver tumor universal normal control PRO21434 liver tumoruniversal normal control

Example 17 Fetal Hemoglobin Induction in an Erythroblastic Cell Line(Assay 107)

[0459] This assay is useful for screening PRO polypeptides for theability to induce the switch from adult hemoglobin to fetal hemoglobinin an erythroblastic cell line. Molecules testing positive in this assayare expected to be useful for therapeutically treating various mammalianhemoglobin-associated disorders such as the various thalassemias. Theassay is performed as follows. Erythroblastic cells are plated instandard growth medium at 1000 cells/well in a 96 well format. PROpolypeptides are added to the growth medium at a concentration of 0.2%or 2% and the cells are incubated for 5 days at 37° C. As a positivecontrol, cells are treated with 100 μm hemin and as a negative control,the cells are untreated. After 5 days, cell lysates are prepared andanalyzed for the expression of gamma globin (a fetal marker). A positivein the assay is a gamma globin level at least 2-fold above the negativecontrol.

[0460] PRO20080 polypeptide tested positive in this assay.

Example 18 Microarray Analysis to Detect Overexpression of PROPolypeptides in HUVEC Cells Treated with Growth Factors

[0461] This assay is designed to determine whether PRO polypeptides ofthe present invention show the ability to induce angiogenesis bystimulating endothelial cell tube formation in HUVEC cells.

[0462] Nucleic acid microarrays, often containing thousands of genesequences, are useful for identifying differentially expressed genes intissues exposed to various stimuli (e.g., growth factors) as compared totheir normal, unexposed counterparts. Using nucleic acid microarrays,test and control mRNA samples from test and control tissue samples arereverse transcribed and labeled to generate cDNA probes. The cDNA probesare then hybridized to an array of nucleic acids immobilized on a solidsupport. The array is configured such that the sequence and position ofeach member of the array is known. Hybridization of a labeled probe witha particular array member indicates that the sample from which the probewas derived expresses that gene. If the hybridization signal of a probefrom a test (exposed tissue) sample is greater than hybridization signalof a probe from a control (normal, unexposed tissue) sample, the gene orgenes overexpressed in the exposed tissue are identified. Theimplication of this result is that an overexpressed protein in anexposed tissue may be involved in the functional changes within thetissue following exposure to the stimuli (e.g., tube formation).

[0463] The methodology of hybridization of nucleic acids and microarraytechnology is well known in the art. In the present example, thespecific preparation of nucleic acids for hybridization and probes,slides, and hybridization conditions are all detailed in U.S.Provisional Patent Application Serial No. 60/193,767, filed on Mar. 31,2000 and which is herein incorporated by reference.

[0464] In the present example, HUVEC cells grown in either collagen gelsor fibrin gels were induced to form tubes by the addition of variousgrowth factors. Specifically, collagen gels were prepared as describedpreviously in Yang et al., American J. Pathology, 1999, 155(3):887-895and Xin et al.,American J. Pathology, 2001, 158(3): 1111-1120. Followinggelation of the HUVEC cells, 1×basal medium containing M199 supplementedwith 1%FBS, 1×ITS, 2 mM L-glutamine, 50 μg/ml ascorbic acid, 26.5 mMNaHCO₃, 100 U/ml penicillin and 100 U/ml streptomycin was added. Tubeformation was elicited by the inclusion in the culture media of either amixture of phorbol myrsitate acetate (50 nM), vascular endothelial cellgrowth factor (40 ng/ml) and basic fibroblast growth factor (40 ng/ml)(“PMA growth factor mix”) or hepatocyte growth factor (40 ng/ml) andvascular endothelial cell growth factor (40 ng/ml) (HGF/VEGF mix) forthe indicated period of time. Fibrin Gels were prepared by suspendingHuvec (4×10⁵ cells/ml) in M199 containing 1% fetal bovine serum(Hyclone) and human fibrinogen (2.5mg/ml). Thrombin (50 U/ml) was thenadded to the fibrinogen suspension at a ratio of 1 part thrombinsolution:30 parts fibrinogen suspension. The solution was then layeredonto 10 cm tissue culture plates (total volume: 15 ml/plate) and allowedto solidify at 37° C. for 20 min. Tissue culture media (10 ml of BMcontaining PMA (50 nM), bFGF (40ng/ml) and VEGF (40 ng/ml)) was thenadded and the cells incubated at 37° C. in 5% CO₂ in air for theindicated period of time.

[0465] Total RNA was extracted from the HUVEC cells incubated for 0, 4,8, 24, 40 and 50 hours in the different matrix and media combinationsusing a TRIzol extraction followed by a second purification usingRNAeasy Mini Kit (Qiagen). The total RNA was used to prepare cRNA whichwas then hybridized to the microarrays.

[0466] In the present experiments, nucleic acid probes derived from theherein described PRO polypeptide-encoding nucleic acid sequences wereused in the creation of the microarray and RNA from the HUVEC cellsdescribed above were used for the hybridization thereto. Pairwisecomparisons were made using time 0 chips as a baseline. Three replicatesamples were analyzed for each experimental condition and time. Hencethere were 3 time 0 samples for each treatment and 3 replicates of eachsuccessive time point. Therefore, a 3 by 3 comparison was performed foreach time point compared against each time 0 point. This resulted in 9comparisons per time point. Only those genes that had increasedexpression in all three non-time-0 replicates in each of the differentmatrix and media combinations as compared to any of the three time zeroreplicates were considered positive. Although this stringent method ofdata analysis does allow for false negatives, it minimizes falsepositives.

[0467] PRO281, PRO 1560, PRO189, PRO4499, PRO6308, PRO6000, PRO 10275,PRO21207, PRO20933,and PRO34274 tested positive in this assay.

Example 19 Tumor Versus Normal Differential Tissue ExpressionDistribution

[0468] Oligonucleotide probes were constructed from some of the PROpolypeptide-encoding nucleotide sequences shown in the accompanyingfigures for use in quantitative PCR amplification reactions. Theoligonucleotide probes were chosen so as to give an approximately200-600 base pair amplified fragment from the 3′ end of its associatedtemplate in a standard PCR reaction. The oligonucleotide probes wereemployed in standard quantitative PCR amplification reactions with cDNAlibraries isolated from different human tumor and normal human tissuesamples and analyzed by agarose gel electrophoresis so as to obtain aquantitative determination of the level of expression of the PROpolypeptide-encoding nucleic acid in the various tumor and normaltissues tested. β-actin was used as a control to assure that equivalentamounts of nucleic acid was used in each reaction. Identification of thedifferential expression of the PRO polypeptide-encoding nucleic acid inone or more tumor tissues as compared to one or more normal tissues ofthe same tissue type renders the molecule useful diagnostically for thedetermination of the presence or absence of tumor in a subject suspectedof possessing a tumor as well as therapeutically as a target for thetreatment of a tumor in a subject possessing such a tumor. These assaysprovided the following results:

[0469] (1) DNA161005-2943 molecule is very highly expressed in humanumblilical vein endothelial cells (HUVEC), substantia niagra,hippocampus and dendrocytes; highly expressed in lymphoblasts; expressedin spleen, prostate, uterus and macrophages; and is weakly expressed incartilage and heart. Among a panel of normal and tumor tissues examined,it is expressed in esophageal tumor, and is not expressed in normalesophagus, normal stomach, stomach tumor, normal kidney, kidney tumor,normal lung, lung tumor, normal rectum, rectal tumor, normal liver andliver tumor.

[0470] (2) DNA170245-3053 molecule is highly expressed in cartilage,testis, adrenal gland, and uterus, and not expressed in HUVEC, colontumor, heart, placenta, bone marrow, spleen and aortic endothelialcells. In a panel of tumor and normal tissue samples examined, theDNA170245-3053 molecule was found to be expressed in normal esophagusand esophagial tumor, expressed in normal stomach and in stomach tumor,not expressed in normal kidney, but expressed in kidney tumor, notexpressed in normal lung, but expressed in lung tumor, not expressed innormal rectum nor in rectal tumor, and not expressed in normal liver,but is expressed in liver tumor.

[0471] (3) DNA173157-2981 molecule is significantly expressed in thefollowing tissues: cartilage, testis, HUVEC, heart, placenta, bonemarrow, adrenal gland, prostate, spleen, aortic endothelial cells, anduterus. When these assays were conducted on a tumor tissue panel, it wasfound that the DNA 173157-2981 molecule is significantly expressed inthe following tissues: normal esophagus and esophagial tumor, normalstomach and stomach tumor, normal kidney and kidney tumor, normal lungand lung tumor, normal rectum and rectal tumor, normal liver and livertumor, and colon tumor.

[0472] (4) DNA175734-2985 molecule is significantly expressed in theadrenal gland and the uterus. The DNA 175734-2985 molecule is notsignificantly expressed in the following tissues: cartilage, testis,HUVEC, colon tumor, heart, placenta, bone marrow, prostate, spleen andaortic endothelial cells. Screening of a tumor panel revealed thatDNA175734-2985 is significantly expressed in normal esophagus but not inesophagial tumor. Similarly, while highly expressed in normal rectum,DNA175734-2985 is expressed to a lesser extent in rectal tumor. DNA175734-2985 is expressed equally in normal stomach and stomach tumor aswell as normal liver and liver tumor. While not expressed in normalkidney, DNA 175734-2985 is highly expressed in kidney tumor.

[0473] (5) DNA 176108-3040 molecule is highly expressed in prostate anduterus, expressed in cartilage, testis, heart, placenta, bone marrow,adrenal gland and spleen, and not significantly expressed in HUVEC,colon tumor, and aortic endothelial cells. In a panel of tumor andnormal tissue samples examined, the DNA 176108-3040 molecule was foundto be highly expressed in normal esophagus, but expressed at lowerlevels in esophagial tumor, highly expressed in normal stomach, andexpressed at a lower level in stomach tumor, expressed in kidney and inkidney tumor, expressed in normal rectum and at a lower level in rectaltumor, and expressed in normal liver and not expressed in liver tumor.

[0474] (6) DNA191064-3069 molecule is significantly expressed in thefollowing tissues: cartilage, testis, HUVEC, heart, placenta, bonemarrow, adrenal gland, prostate, spleen, aortic endothelial cells, anduterus and not significantly expressed in colon tumor. In a panel oftumor and normal tissue samples, the DNA191064-3069 molecule was foundto be expressed in normal esophagus and in esophagial tumors, expressedin normal stomach and in stomach tumors, expressed in normal kidney andin kidney tumors, expressed in normal lung and in lung tumors, expressedin normal rectum and in rectal tumors, expressed in normal liver and inliver tumors.

[0475] (7) DNA 194909-3013 molecule is highly expressed in placenta, andexpressed in cartilage, testis, HUVEC, colon tumor, heart, bone marrow,adrenal gland, prostate, spleen, aortic endothelial cells and uterus. Ina panel of tumor and normal tissue samples examined, the DNA 194909-3013molecule was found to be expressed in normal esophagus and expressed ata lower level in esophagial tumor, not expressed in normal stomach norstomach tumor, expressed in normal kidney and kidney tumor, expressed innormal lung and lung tumor, expressed in normal rectum and rectal tumor,and not expressed in normal liver, but is expressed in liver tumor.

[0476] (8) The PRO34009 encoding genes of the invention (DNA203532-3029)were screened in normal tissues and the following primary tumors and theresulting values are reported below.

[0477] Tumor Panel

[0478] PRO34009 encoding genes were expressed 39.3 fold higher in lungtumor than normal lung. It is expressed 9.5 fold higher in esophagialtumors than normal esophagus. It is expressed 6.7 fold higher in kidneytumor than normal kidney. It is expressed 4.0 fold higher in colon tumorthan normal colon. It is expressed 2.7 fold higher in stomach tumor thannormal stomach. It is expressed at similar levels in normal rectum andrectal tumor, normal liver and liver tumor, normal uterus and uterinetumor.

[0479] Normal Panel

[0480] For the normal tissue values, the normal tissue with the highestexpression, in this case normal thymus, was given a value of 1 and allother normal tissues were given a value of less than 1,and described asexpressed, weakly expressed or not expressed, based on their expressionrelative to thymus. PRO34009 encoding genes were expressed in normalthymus. It is weakly expressed in lymphoblast, spleen, heart, fetallimb, fetal lung, placenta, HUVEC, testis, fetal kidney, uterus,prostate, macrophage, substantia nigra, hippocampus, liver, skin,esophagus, stomach, rectum, kidney, thyroid, skeletal muscle, or fetalarticular cartilage. It is not expressed in bone marrow, fetal liver,colon, lung or dendrocytes.

[0481] (9) DNA213858-3060 molecule is not significantly expressed incartilage, testis, HUVEC, colon tumor, heart, placenta, bone marrow,adrenal gland, prostate, spleen, aortic endothelial cells or uterus. Ina panel of tumor and normal tissue samples examined, the DNA213858-3060molecule was found to be expressed in normal esophagus and esophagialtumor, expressed in normal stomach and in stomach tumor, expressed innormal kidney and and kidney tumor, expressed in normal lung and in lungtumor, expressed in normal rectum and in rectal tumor, and expressed innormal liver and in liver tumor.

[0482] (10) DNA216676-3083 molecule is significantly expressed in thefollowing tissues: testis, heart, bone marrow, and uterus, and notsignificantly expressed in the following tissues: cartilage, HUVEC,colon tumor, placenta, adrenal gland, prostate, spleen, or aorticendothelial cells In a panel of tumor and normal tissues samplesexamined, the DNA216676-3083 molecule was found to be expressed innormal esophagus and esophagial tumor, not expressed in normal stomach,but is expressed in stomach tumor, not expressed in normal kidney nor inkidney tumor, not expressed in normal lung, but is expressed in lungtumor, not expressed in normal rectum, but is expressed in rectal tumor,and not expressed in normal liver nor in liver tumor.

[0483] (11) DNA222653-3104 molecule is significantly expressed testis,and not significantly expressed in cartilage, HUVEC, colon tumor, heart,placenta, bone marrow, adrenal gland, prostate, spleen, aorticendothelial cells and uterus. In a panel of tumor and normal tissuesamples examined, the DNA22653-3104 molecule was not expressed in normalesophagus, esophagial tumor, normal stomach, stomach tumor, normalkidney, kidney tumor, normal lung, lung tumor, normal rectum, rectaltumor, normal liver and liver tumor.

Example 20 Guinea Pig Vascular Leak (Assay 51)

[0484] This assay is designed to determine whether PRO polypeptides ofthe present invention show the ability to induce vascular permeability.Polypeptides testing positive in this assay are expected to be usefulfor the therapeutic treatment of conditions which would benefit fromenhanced vascular permeability including, for example, conditions whichmay benefit from enhanced local immune system cell infiltration.

[0485] Hairless guinea pigs weighing 350 grams or more were anesthetizedwith Ketamine (75-80 mg/kg) and 5 mg/kg Xylazine intramuscularly. Testsamples containing the PRO polypeptide or a physiological buffer withoutthe test polypeptide are injected into skin on the back of the testanimals with 100 μl per injection site intradermally. There wereapproximately 16-24 injection sites per animal. One ml of Evans blue dye(1% in PBS) is then injected intracardially. Skin vascular permeabilityresponses to the compounds (i.e., blemishes at the injection sites ofinjection) are visually scored by measuring the diameter (in mm) ofblue-colored leaks from the site of injection at 1 and 6 hours postadministration of the test materials. The mm diameter of blueness at thesite of injection is observed and recorded as well as the severity ofthe vascular leakage. Blemishes of at least 5 mm in diameter areconsidered positive for the assay when testing purified proteins, beingindicative of the ability to induce vascular leakage or permeability. Aresponse greater than 7 mm diameter is considered positive forconditioned media samples. Human VEGF at 0.1 μg/100 μl is used as apositive control, inducing a response of 15-23 mm diameter.

[0486] PRO19822 polypeptides tested positive in this assay.

Example 21 Skin Vascular Permeability Assay (Assay 64)

[0487] This assay shows that certain polypeptides of the inventionstimulate an immune response and induce inflammation by inducingmononuclear cell, eosinophil and PMN infiltration at the site ofinjection of the animal. Compounds which stimulate an immune responseare useful therapeutically where stimulation of an immune response isbeneficial. This skin vascular permeability assay is conducted asfollows. Hairless guinea pigs weighing 350 grams or more areanesthetized with ketamine (75-80 mg/Kg) and 5 mg/Kg xylazineintramuscularly (IM). A sample of purified polypeptide of the inventionor a conditioned media test sample is injected intradermally onto thebacks of the test animals with 100 μl per injection site: It is possibleto have about 10-30, preferably about 16-24, injection sites per animal.One μl of Evans blue dye (1% in physiologic buffered saline) is injectedintracardially. Blemishes at the injection sites are then measured (mmdiameter) at 1 hr and 6 hr post injection. Animals were sacrificed at 6hrs after injection. Each skin injection site is biopsied and fixed informalin. The skins are then prepared for histopathologic evaluation.Each site is evaluated for inflammatory cell infiltration into the skin.Sites with visible inflammatory cell inflammation are scored aspositive. Inflammatory cells may be neutrophilic, eosinophilic,monocytic or lymphocytic. At least a minimal perivascular infiltrate atthe injection site is scored as positive, no infiltrate at the site ofinjection is scored as negative.

[0488] PRO19822 polypeptide tested positive in this assay.

SEQUENCE LISTING

[0489] <110> Baker,Kevin

[0490] Eaton,Dan

[0491] Filvaroff,Ellen

[0492] Goddard,Audrey

[0493] Grimaldi,J. Christopher

[0494] Gurney,Austin

[0495] Smith,Victoria

[0496] Stephan,Jean-Phillippe

[0497] Watanbe,Colin

[0498] Wood,William

[0499] Zhang,Zemin

[0500] Fong,Sherman

[0501] <120> SECRETED AND TRANSMEMBRANE POLYPEPTIDES AND NUCLEIC ACIDSENCODING THE SAME

[0502] <130> P3630R1C41

[0503] <150> 10/197942

[0504] <151> 2002-07-18

[0505] <150> 60/059114

[0506] <151> 1997-09-17

[0507] <150> 60/063046

[0508] <151> 1997-10-24

[0509] <150> 60/065027

[0510] <151> 1997-11-10

[0511] <150> 60/079689

[0512] <151> 1998-03-27

[0513] <150> 60/086478

[0514] <151> 1998-05-22

[0515] <150> 60/087607

[0516] <151> 1998-06-02

[0517] <150> 60/089801

[0518] <151> 1998-06-18

[0519] <150> 60/090557

1 116 1 1943 DNA Homo Sapien 1 cggacgcgtg ggtgcgaggc gaaggtgaccggggaccgag catttcagat 50 ctgctcggta gacctggtgc accaccacca tgttggctgcaaggctggtg 100 tgtctccgga cactaccttc tagggttttc cacccagctt tcaccaaggc150 ctcccctgtt gtgaagaatt ccatcacgaa gaatcaatgg ctgttaacac 200ctagcaggga atatgccacc aaaacaagaa ttgggatccg gcgtgggaga 250 actggccaagaactcaaaga ggcagcattg gaaccatcga tggaaaaaat 300 atttaaaatt gatcagatgggaagatggtt tgttgctgga ggggctgctg 350 ttggtcttgg agcattgtgc tactatggcttgggactgtc taatgagatt 400 ggagctattg aaaaggctgt aatttggcct cagtatgtcaaggatagaat 450 tcattccacc tatatgtact tagcagggag tattggttta acagctttgt500 ctgccatagc aatcagcaga acgcctgttc tcatgaactt catgatgaga 550ggctcttggg tgacaattgg tgtgaccttt gcagccatgg ttggagctgg 600 aatgctggtacgatcaatac catatgacca gagcccaggc ccaaagcatc 650 ttgcttggtt gctacattctggtgtgatgg gtgcagtggt ggctcctctg 700 acaatattag ggggtcctct tctcatcagagctgcatggt acacagctgg 750 cattgtggga ggcctctcca ctgtggccat gtgtgcgcccagtgaaaagt 800 ttctgaacat gggtgcaccc ctgggagtgg gcctgggtct cgtctttgtg850 tcctcattgg gatctatgtt tcttccacct accaccgtgg ctggtgccac 900tctttactca gtggcaatgt acggtggatt agttcttttc agcatgttcc 950 ttctgtatgatacccagaaa gtaatcaagc gtgcagaagt atcaccaatg 1000 tatggagttc aaaaatatgatcccattaac tcgatgctga gtatctacat 1050 ggatacatta aatatattta tgcgagttgcaactatgctg gcaactggag 1100 gcaacagaaa gaaatgaagt gactcagctt ctggcttctctgctacatca 1150 aatatcttgt ttaatggggc agatatgcat taaatagttt gtacaagcag1200 ctttcgttga agtttagaag ataagaaaca tgtcatcata tttaaatgtt 1250ccggtaatgt gatgcctcag gtctgccttt ttttctggag aataaatgca 1300 gtaatcctctcccaaataag cacacacatt ttcaattctc atgtttgagt 1350 gattttaaaa tgttttggtgaatgtgaaaa ctaaagtttg tgtcatgaga 1400 atgtaagtct tttttctact ttaaaatttagtaggttcac tgagtaacta 1450 aaatttagca aacctgtgtt tgcatatttt tttggagtgcagaatattgt 1500 aattaatgtc ataagtgatt tggagctttg gtaaagggac cagagagaag1550 gagtcacctg cagtcttttg tttttttaaa tacttagaac ttagcacttg 1600tgttattgat tagtgaggag ccagtaagaa acatctgggt atttggaaac 1650 aagtggtcattgttacattc atttgctgaa cttaacaaaa ctgttcatcc 1700 tgaaacaggc acaggtgatgcattctcctg ctgttgcttc tcagtgctct 1750 ctttccaata tagatgtggt catgtttgacttgtacagaa tgttaatcat 1800 acagagaatc cttgatggaa ttatatatgt gtgttttacttttgaatgtt 1850 acaaaaggaa ataactttaa aactattctc aagagaaaat attcaaagca1900 tgaaatatgt tgctttttcc agaatacaaa cagtatactc atg 1943 2 345 PRT HomoSapien 2 Met Leu Ala Ala Arg Leu Val Cys Leu Arg Thr Leu Pro Ser Arg 1 510 15 Val Phe His Pro Ala Phe Thr Lys Ala Ser Pro Val Val Lys Asn 20 2530 Ser Ile Thr Lys Asn Gln Trp Leu Leu Thr Pro Ser Arg Glu Tyr 35 40 45Ala Thr Lys Thr Arg Ile Gly Ile Arg Arg Gly Arg Thr Gly Gln 50 55 60 GluLeu Lys Glu Ala Ala Leu Glu Pro Ser Met Glu Lys Ile Phe 65 70 75 Lys IleAsp Gln Met Gly Arg Trp Phe Val Ala Gly Gly Ala Ala 80 85 90 Val Gly LeuGly Ala Leu Cys Tyr Tyr Gly Leu Gly Leu Ser Asn 95 100 105 Glu Ile GlyAla Ile Glu Lys Ala Val Ile Trp Pro Gln Tyr Val 110 115 120 Lys Asp ArgIle His Ser Thr Tyr Met Tyr Leu Ala Gly Ser Ile 125 130 135 Gly Leu ThrAla Leu Ser Ala Ile Ala Ile Ser Arg Thr Pro Val 140 145 150 Leu Met AsnPhe Met Met Arg Gly Ser Trp Val Thr Ile Gly Val 155 160 165 Thr Phe AlaAla Met Val Gly Ala Gly Met Leu Val Arg Ser Ile 170 175 180 Pro Tyr AspGln Ser Pro Gly Pro Lys His Leu Ala Trp Leu Leu 185 190 195 His Ser GlyVal Met Gly Ala Val Val Ala Pro Leu Thr Ile Leu 200 205 210 Gly Gly ProLeu Leu Ile Arg Ala Ala Trp Tyr Thr Ala Gly Ile 215 220 225 Val Gly GlyLeu Ser Thr Val Ala Met Cys Ala Pro Ser Glu Lys 230 235 240 Phe Leu AsnMet Gly Ala Pro Leu Gly Val Gly Leu Gly Leu Val 245 250 255 Phe Val SerSer Leu Gly Ser Met Phe Leu Pro Pro Thr Thr Val 260 265 270 Ala Gly AlaThr Leu Tyr Ser Val Ala Met Tyr Gly Gly Leu Val 275 280 285 Leu Phe SerMet Phe Leu Leu Tyr Asp Thr Gln Lys Val Ile Lys 290 295 300 Arg Ala GluVal Ser Pro Met Tyr Gly Val Gln Lys Tyr Asp Pro 305 310 315 Ile Asn SerMet Leu Ser Ile Tyr Met Asp Thr Leu Asn Ile Phe 320 325 330 Met Arg ValAla Thr Met Leu Ala Thr Gly Gly Asn Arg Lys Lys 335 340 345 3 1110 DNAHomo Sapien 3 ccaatcgccc ggtgcggtgg tgcagggtct cgggctagtc atggcgtccc 50cgtctcggag actgcagact aaaccagtca ttacttgttt caagagcgtt 100 ctgctaatctacacttttat tttctggatc actggcgtta tccttcttgc 150 agttggcatt tggggcaaggtgagcctgga gaattacttt tctcttttaa 200 atgagaaggc caccaatgtc cccttcgtgctcattgctac tggtaccgtc 250 attattcttt tgggcacctt tggttgtttt gctacctgccgagcttctgc 300 atggatgcta aaactgtatg caatgtttct gactctcgtt tttttggtcg350 aactggtcgc tgccatcgta ggatttgttt tcagacatga gattaagaac 400agctttaaga ataattatga gaaggctttg aagcagtata actctacagg 450 agattatagaagccatgcag tagacaagat ccaaaatacg ttgcattgtt 500 gtggtgtcac cgattatagagattggacag atactaatta ttactcagaa 550 aaaggatttc ctaagagttg ctgtaaacttgaagattgta ctccacagag 600 agatgcagac aaagtaaaca atgaaggttg ttttataaaggtgatgacca 650 ttatagagtc agaaatggga gtcgttgcag gaatttcctt tggagttgct700 tgcttccaac tgattggaat ctttctcgcc tactgccwct ctcgtgccat 750aacaaataac cagtatgaga tagtgtaacc caatgtatct gtgggcctat 800 tcctctctacctttaaggac atttagggtc ccccctgtga attagaaagt 850 tgcttggctg gagaactgacaacactactt actgatagac caaaaaacta 900 caccagtagg ttgattcaat caagatgtatgtagacctaa aactacacca 950 ataggctgat tcaatcaaga tccgtgctcg cagtgggctgattcaatcaa 1000 gatgtatgtt tgctatgttc taagtccacc ttctatccca ttcatgttag1050 atcgttgaaa ccctgtatcc ctctgaaaca ctggaagagc tagtaaattg 1100taaatgaagt 1110 4 245 PRT Homo Sapien unsure 233 unknown amino acid 4Met Ala Ser Pro Ser Arg Arg Leu Gln Thr Lys Pro Val Ile Thr 1 5 10 15Cys Phe Lys Ser Val Leu Leu Ile Tyr Thr Phe Ile Phe Trp Ile 20 25 30 ThrGly Val Ile Leu Leu Ala Val Gly Ile Trp Gly Lys Val Ser 35 40 45 Leu GluAsn Tyr Phe Ser Leu Leu Asn Glu Lys Ala Thr Asn Val 50 55 60 Pro Phe ValLeu Ile Ala Thr Gly Thr Val Ile Ile Leu Leu Gly 65 70 75 Thr Phe Gly CysPhe Ala Thr Cys Arg Ala Ser Ala Trp Met Leu 80 85 90 Lys Leu Tyr Ala MetPhe Leu Thr Leu Val Phe Leu Val Glu Leu 95 100 105 Val Ala Ala Ile ValGly Phe Val Phe Arg His Glu Ile Lys Asn 110 115 120 Ser Phe Lys Asn AsnTyr Glu Lys Ala Leu Lys Gln Tyr Asn Ser 125 130 135 Thr Gly Asp Tyr ArgSer His Ala Val Asp Lys Ile Gln Asn Thr 140 145 150 Leu His Cys Cys GlyVal Thr Asp Tyr Arg Asp Trp Thr Asp Thr 155 160 165 Asn Tyr Tyr Ser GluLys Gly Phe Pro Lys Ser Cys Cys Lys Leu 170 175 180 Glu Asp Cys Thr ProGln Arg Asp Ala Asp Lys Val Asn Asn Glu 185 190 195 Gly Cys Phe Ile LysVal Met Thr Ile Ile Glu Ser Glu Met Gly 200 205 210 Val Val Ala Gly IleSer Phe Gly Val Ala Cys Phe Gln Leu Ile 215 220 225 Gly Ile Phe Leu AlaTyr Cys Xaa Ser Arg Ala Ile Thr Asn Asn 230 235 240 Gln Tyr Glu Ile Val245 5 1373 DNA Homo Sapien 5 ggggccgcgg tctagggcgg ctacgtgtgt tgccatagcgaccattttgc 50 attaactggt tggtagcttc tatcctgggg gctgagcgac tgcgggccag 100ctcttcccct actccctctc ggctccttgt ggcccaaagg cctaaccggg 150 gtccggcggtctggcctagg gatcttcccc gttgcccctt tggggcggga 200 tggctgcgga agaagaagacgaggtggagt gggtagtgga gagcatcgcg 250 gggttcctgc gaggcccaga ctggtccatccccatcttgg actttgtgga 300 acagaaatgt gaagttaact gcaaaggagg gcatgtgataactccaggaa 350 gcccagagcc ggtgattttg gtggcctgtg ttccccttgt ttttgatgat400 gaagaagaaa gcaaattgac ctatacagag attcatcagg aatacaaaga 450actagttgaa aagctgttag aaggttacct caaagaaatt ggaattaatg 500 aagatcaatttcaagaagca tgcacttctc ctcttgcaaa gacccataca 550 tcacaggcca ttttgcaacctgtgttggca gcagaagatt ttactatctt 600 taaagcaatg atggtccaga aaaacattgaaatgcagctg caagccattc 650 gaataattca agagagaaat ggtgtattac ctgactgcttaaccgatggc 700 tctgatgtgg tcagtgacct tgaacacgaa gagatgaaaa tcctgaggga750 agttcttaga aaatcaaaag aggaatatga ccaggaagaa gaaaggaaga 800ggaaaaaaca gttatcagag gctaaaacag aagagcccac agtgcattcc 850 agtgaagctgcaataatgaa taattcccaa ggggatggtg aacattttgc 900 acacccaccc tcagaagttaaaatgcattt tgctaatcag tcaatagaac 950 ctttgggaag aaaagtggaa aggtctgaaacttcctccct cccacaaaaa 1000 ggcctgaaga ttcctggctt agagcatgcg agcattgaaggaccaatagc 1050 aaacttatca gtacttggaa cagaagaact tcggcaacga gaacactatc1100 tcaagcagaa gagagataag ttgatgtcca tgagaaagga tatgaggact 1150aaacagatac aaaatatgga gcagaaagga aaacccactg gggaggtaga 1200 ggaaatgacagagaaaccag aaatgacagc agaggagaag caaacattac 1250 taaagaggag attgcttgcagagaaactca aagaagaagt tattaataag 1300 taataattaa gaacaattta acaaaatggaagttcaaatt gtcttaaaaa 1350 taaattattt agtccttaca ctg 1373 6 367 PRT HomoSapien 6 Met Ala Ala Glu Glu Glu Asp Glu Val Glu Trp Val Val Glu Ser 1 510 15 Ile Ala Gly Phe Leu Arg Gly Pro Asp Trp Ser Ile Pro Ile Leu 20 2530 Asp Phe Val Glu Gln Lys Cys Glu Val Asn Cys Lys Gly Gly His 35 40 45Val Ile Thr Pro Gly Ser Pro Glu Pro Val Ile Leu Val Ala Cys 50 55 60 ValPro Leu Val Phe Asp Asp Glu Glu Glu Ser Lys Leu Thr Tyr 65 70 75 Thr GluIle His Gln Glu Tyr Lys Glu Leu Val Glu Lys Leu Leu 80 85 90 Glu Gly TyrLeu Lys Glu Ile Gly Ile Asn Glu Asp Gln Phe Gln 95 100 105 Glu Ala CysThr Ser Pro Leu Ala Lys Thr His Thr Ser Gln Ala 110 115 120 Ile Leu GlnPro Val Leu Ala Ala Glu Asp Phe Thr Ile Phe Lys 125 130 135 Ala Met MetVal Gln Lys Asn Ile Glu Met Gln Leu Gln Ala Ile 140 145 150 Arg Ile IleGln Glu Arg Asn Gly Val Leu Pro Asp Cys Leu Thr 155 160 165 Asp Gly SerAsp Val Val Ser Asp Leu Glu His Glu Glu Met Lys 170 175 180 Ile Leu ArgGlu Val Leu Arg Lys Ser Lys Glu Glu Tyr Asp Gln 185 190 195 Glu Glu GluArg Lys Arg Lys Lys Gln Leu Ser Glu Ala Lys Thr 200 205 210 Glu Glu ProThr Val His Ser Ser Glu Ala Ala Ile Met Asn Asn 215 220 225 Ser Gln GlyAsp Gly Glu His Phe Ala His Pro Pro Ser Glu Val 230 235 240 Lys Met HisPhe Ala Asn Gln Ser Ile Glu Pro Leu Gly Arg Lys 245 250 255 Val Glu ArgSer Glu Thr Ser Ser Leu Pro Gln Lys Gly Leu Lys 260 265 270 Ile Pro GlyLeu Glu His Ala Ser Ile Glu Gly Pro Ile Ala Asn 275 280 285 Leu Ser ValLeu Gly Thr Glu Glu Leu Arg Gln Arg Glu His Tyr 290 295 300 Leu Lys GlnLys Arg Asp Lys Leu Met Ser Met Arg Lys Asp Met 305 310 315 Arg Thr LysGln Ile Gln Asn Met Glu Gln Lys Gly Lys Pro Thr 320 325 330 Gly Glu ValGlu Glu Met Thr Glu Lys Pro Glu Met Thr Ala Glu 335 340 345 Glu Lys GlnThr Leu Leu Lys Arg Arg Leu Leu Ala Glu Lys Leu 350 355 360 Lys Glu GluVal Ile Asn Lys 365 7 932 DNA Homo Sapien unsure 911 unknown base 7gggaacggaa aatggcgcct cacggcccgg gtagtcttac gaccctggtg 50 ccctgggctgccgccctgct cctcgctctg ggcgtggaaa gggctctggc 100 gctacccgag atatgcacccaatgtccagg gagcgtgcaa aatttgtcaa 150 aagtggcctt ttattgtaaa acgacacgagagctaatgct gcatgcccgt 200 tgctgcctga atcagaaggg caccatcttg gggctggatctccagaactg 250 ttctctggag gaccctggtc caaactttca tcaggcacat accactgtca300 tcatagacct gcaagcaaac cccctcaaag gtgacttggc caacaccttc 350cgtggcttta ctcagctcca gactctgata ctgccacaac atgtcaactg 400 tcctggaggaattaatgcct ggaatactat cacctcttat atagacaacc 450 aaatctgtca agggcaaaagaacctttgca ataacactgg ggacccagaa 500 atgtgtcctg agaatggatc ttgtgtacctgatggtccag gtcttttgca 550 gtgtgtttgt gctgatggtt tccatggata caagtgtatgcgccagggct 600 cgttctcact gcttatgttc ttcgggattc tgggagccac cactctatcc650 gtctccattc tgctttgggc gacccagcgc cgaaaagcca agacttcatg 700aactacatag gtcttaccat tgacctaaga tcaatctgaa ctatcttagc 750 ccagtcagggagctctgctt cctagaaagg catctttcgc cagtggattc 800 gcctcaaggt tgaggccgccattggaagat gaaaaattgc actcccttgg 850 tgtagacaaa taccagttcc cattggtgttgttgcctata ataaacactt 900 tttctttttt naaaaaaaaa aaaaaaaaaa aa 932 8 229PRT Homo Sapien 8 Met Ala Pro His Gly Pro Gly Ser Leu Thr Thr Leu ValPro Trp 1 5 10 15 Ala Ala Ala Leu Leu Leu Ala Leu Gly Val Glu Arg AlaLeu Ala 20 25 30 Leu Pro Glu Ile Cys Thr Gln Cys Pro Gly Ser Val Gln AsnLeu 35 40 45 Ser Lys Val Ala Phe Tyr Cys Lys Thr Thr Arg Glu Leu Met Leu50 55 60 His Ala Arg Cys Cys Leu Asn Gln Lys Gly Thr Ile Leu Gly Leu 6570 75 Asp Leu Gln Asn Cys Ser Leu Glu Asp Pro Gly Pro Asn Phe His 80 8590 Gln Ala His Thr Thr Val Ile Ile Asp Leu Gln Ala Asn Pro Leu 95 100105 Lys Gly Asp Leu Ala Asn Thr Phe Arg Gly Phe Thr Gln Leu Gln 110 115120 Thr Leu Ile Leu Pro Gln His Val Asn Cys Pro Gly Gly Ile Asn 125 130135 Ala Trp Asn Thr Ile Thr Ser Tyr Ile Asp Asn Gln Ile Cys Gln 140 145150 Gly Gln Lys Asn Leu Cys Asn Asn Thr Gly Asp Pro Glu Met Cys 155 160165 Pro Glu Asn Gly Ser Cys Val Pro Asp Gly Pro Gly Leu Leu Gln 170 175180 Cys Val Cys Ala Asp Gly Phe His Gly Tyr Lys Cys Met Arg Gln 185 190195 Gly Ser Phe Ser Leu Leu Met Phe Phe Gly Ile Leu Gly Ala Thr 200 205210 Thr Leu Ser Val Ser Ile Leu Leu Trp Ala Thr Gln Arg Arg Lys 215 220225 Ala Lys Thr Ser 9 2482 DNA Homo Sapien 9 gggggagaag gcggccgagccccagctctc cgagcaccgg gtcggaagcc 50 gcgacccgag ccgcgcagga agctgggaccggaacctcgg cggacccggc 100 cccacccaac tcacctgcgc aggtcaccag caccctcggaacccagaggc 150 ccgcgctctg aaggtgaccc ccctggggag gaaggcgatg gcccctgcga200 ggacgatggc ccgcgcccgc ctcgccccgg ccggcatccc tgccgtcgcc 250ttgtggcttc tgtgcacgct cggcctccag ggcacccagg ccgggccacc 300 gcccgcgccccctgggctgc ccgcgggagc cgactgcctg aacagcttta 350 ccgccggggt gcctggcttcgtgctggaca ccaacgcctc ggtcagcaac 400 ggagctacct tcctggagtc ccccaccgtgcgccggggct gggactgcgt 450 gcgcgcctgc tgcaccaccc agaactgcaa cttggcgctagtggagctgc 500 agcccgaccg cggggaggac gccatcgccg cctgcttcct catcaactgc550 ctctacgagc agaacttcgt gtgcaagttc gcgcccaggg agggcttcat 600caactacctc acgagggaag tgtaccgctc ctaccgccag ctgcggaccc 650 agggctttggagggtctggg atccccaagg cctgggcagg catagacttg 700 aaggtacaac cccaggaacccctggtgctg aaggatgtgg aaaacacaga 750 ttggcgccta ctgcggggtg acacggatgtcagggtagag aggaaagacc 800 caaaccaggt ggaactgtgg ggactcaagg aaggcacctacctgttccag 850 ctgacagtga ctagctcaga ccacccagag gacacggcca acgtcacagt900 cactgtgctg tccaccaagc agacagaaga ctactgcctc gcatccaaca 950aggtgggtcg ctgccggggc tctttcccac gctggtacta tgaccccacg 1000 gagcagatctgcaagagttt cgtttatgga ggctgcttgg gcaacaagaa 1050 caactacctt cgggaagaagagtgcattct agcctgtcgg ggtgtgcaag 1100 gtgggccttt gagaggcagc tctggggctcaggcgacttt cccccagggc 1150 ccctccatgg aaaggcgcca tccagtgtgc tctggcacctgtcagcccac 1200 ccagttccgc tgcagcaatg gctgctgcat cgacagtttc ctggagtgtg1250 acgacacccc caactgcccc gacgcctccg acgaggctgc ctgtgaaaaa 1300tacacgagtg gctttgacga gctccagcgc atccatttcc ccagtgacaa 1350 agggcactgcgtggacctgc cagacacagg actctgcaag gagagcatcc 1400 cgcgctggta ctacaaccccttcagcgaac actgcgcccg ctttacctat 1450 ggtggttgtt atggcaacaa gaacaactttgaggaagagc agcagtgcct 1500 cgagtcttgt cgcggcatct ccaagaagga tgtgtttggcctgaggcggg 1550 aaatccccat tcccagcaca ggctctgtgg agatggctgt cacagtgttc1600 ctggtcatct gcattgtggt ggtggtagcc atcttgggtt actgcttctt 1650caagaaccag agaaaggact tccacggaca ccaccaccac ccaccaccca 1700 cccctgccagctccactgtc tccactaccg aggacacgga gcacctggtc 1750 tataaccaca ccacccggcccctctgagcc tgggtctcac cggctctcac 1800 ctggccctgc ttcctgcttg ccaaggcagaggcctgggct gggaaaaact 1850 ttggaaccag actcttgcct gtttcccagg cccactgtgcctcagagacc 1900 agggctccag cccctcttgg agaagtctca gctaagctca cgtcctgaga1950 aagctcaaag gtttggaagg agcagaaaac ccttgggcca gaagtaccag 2000actagatgga cctgcctgca taggagtttg gaggaagttg gagttttgtt 2050 tcctctgttcaaagctgcct gtccctaccc catggtgcta ggaagaggag 2100 tggggtggtg tcagaccctggaggccccaa ccctgtcctc ccgagctcct 2150 cttccatgct gtgcgcccag ggctgggaggaaggacttcc ctgtgtagtt 2200 tgtgctgtaa agagttgctt tttgtttatt taatgctgtggcatgggtga 2250 agaggagggg aagaggcctg tttggcctct ctgtcctctc ttcctcttcc2300 cccaagattg agctctctgc ccttgatcag ccccaccctg gcctagacca 2350gcagacagag ccaggagagg ctcagctgca ttccgcagcc cccaccccca 2400 aggttctccaacatcacagc ccagcccacc cactgggtaa taaaagtggt 2450 ttgtggaaaa aaaaaaaaaaaaaaaaaaaa aa 2482 10 529 PRT Homo Sapien 10 Met Ala Pro Ala Arg Thr MetAla Arg Ala Arg Leu Ala Pro Ala 1 5 10 15 Gly Ile Pro Ala Val Ala LeuTrp Leu Leu Cys Thr Leu Gly Leu 20 25 30 Gln Gly Thr Gln Ala Gly Pro ProPro Ala Pro Pro Gly Leu Pro 35 40 45 Ala Gly Ala Asp Cys Leu Asn Ser PheThr Ala Gly Val Pro Gly 50 55 60 Phe Val Leu Asp Thr Asn Ala Ser Val SerAsn Gly Ala Thr Phe 65 70 75 Leu Glu Ser Pro Thr Val Arg Arg Gly Trp AspCys Val Arg Ala 80 85 90 Cys Cys Thr Thr Gln Asn Cys Asn Leu Ala Leu ValGlu Leu Gln 95 100 105 Pro Asp Arg Gly Glu Asp Ala Ile Ala Ala Cys PheLeu Ile Asn 110 115 120 Cys Leu Tyr Glu Gln Asn Phe Val Cys Lys Phe AlaPro Arg Glu 125 130 135 Gly Phe Ile Asn Tyr Leu Thr Arg Glu Val Tyr ArgSer Tyr Arg 140 145 150 Gln Leu Arg Thr Gln Gly Phe Gly Gly Ser Gly IlePro Lys Ala 155 160 165 Trp Ala Gly Ile Asp Leu Lys Val Gln Pro Gln GluPro Leu Val 170 175 180 Leu Lys Asp Val Glu Asn Thr Asp Trp Arg Leu LeuArg Gly Asp 185 190 195 Thr Asp Val Arg Val Glu Arg Lys Asp Pro Asn GlnVal Glu Leu 200 205 210 Trp Gly Leu Lys Glu Gly Thr Tyr Leu Phe Gln LeuThr Val Thr 215 220 225 Ser Ser Asp His Pro Glu Asp Thr Ala Asn Val ThrVal Thr Val 230 235 240 Leu Ser Thr Lys Gln Thr Glu Asp Tyr Cys Leu AlaSer Asn Lys 245 250 255 Val Gly Arg Cys Arg Gly Ser Phe Pro Arg Trp TyrTyr Asp Pro 260 265 270 Thr Glu Gln Ile Cys Lys Ser Phe Val Tyr Gly GlyCys Leu Gly 275 280 285 Asn Lys Asn Asn Tyr Leu Arg Glu Glu Glu Cys IleLeu Ala Cys 290 295 300 Arg Gly Val Gln Gly Gly Pro Leu Arg Gly Ser SerGly Ala Gln 305 310 315 Ala Thr Phe Pro Gln Gly Pro Ser Met Glu Arg ArgHis Pro Val 320 325 330 Cys Ser Gly Thr Cys Gln Pro Thr Gln Phe Arg CysSer Asn Gly 335 340 345 Cys Cys Ile Asp Ser Phe Leu Glu Cys Asp Asp ThrPro Asn Cys 350 355 360 Pro Asp Ala Ser Asp Glu Ala Ala Cys Glu Lys TyrThr Ser Gly 365 370 375 Phe Asp Glu Leu Gln Arg Ile His Phe Pro Ser AspLys Gly His 380 385 390 Cys Val Asp Leu Pro Asp Thr Gly Leu Cys Lys GluSer Ile Pro 395 400 405 Arg Trp Tyr Tyr Asn Pro Phe Ser Glu His Cys AlaArg Phe Thr 410 415 420 Tyr Gly Gly Cys Tyr Gly Asn Lys Asn Asn Phe GluGlu Glu Gln 425 430 435 Gln Cys Leu Glu Ser Cys Arg Gly Ile Ser Lys LysAsp Val Phe 440 445 450 Gly Leu Arg Arg Glu Ile Pro Ile Pro Ser Thr GlySer Val Glu 455 460 465 Met Ala Val Thr Val Phe Leu Val Ile Cys Ile ValVal Val Val 470 475 480 Ala Ile Leu Gly Tyr Cys Phe Phe Lys Asn Gln ArgLys Asp Phe 485 490 495 His Gly His His His His Pro Pro Pro Thr Pro AlaSer Ser Thr 500 505 510 Val Ser Thr Thr Glu Asp Thr Glu His Leu Val TyrAsn His Thr 515 520 525 Thr Arg Pro Leu 11 1899 DNA Homo Sapien 11gtgctgggct ttttcagaca agtgcatctc ctaaccaggt cacatttcag 50 ccgcgacccactctccgcca gtcaccggag gcagaccgcg ggaggagagc 100 tgaggacagc cgcgtgcgcttcgccagcag cggggtggga ggaaggacat 150 taaaatactg cagaagtcaa gacccccccaggtcgaaccc agaccacgat 200 gcgcgccccg ggctgcgggc ggctggtgct gccgctgctgctcctggccg 250 cggcagccct ggccgaaggc gacgccaagg ggctcaagga gggcgagacc300 cccggcaatt tcatggagga cgagcaatgg ctgtcgtcca tctcgcagta 350cagcggcaag atcaagcact ggaaccgctt ccgagacgaa gtggaggatg 400 actatatcaagagctgggag gacaatcagc aaggagatga agccctggat 450 accaccaagg acccctgccagaaggtgaag tgcagccgcc acaaggtgtg 500 cattgcccag ggctaccagc gggccatgtgcatcagtcgc aagaagctgg 550 agcacaggat caagcagccg accgtgaaac tccatggaaacaaagactcc 600 atctgcaagc cctgccacat ggcccagctt gcctctgtct gcggctcaga650 tggccacact tacagctctg tgtgtaagct ggagcaacag gcgtgcctga 700gcagcaagca gctggcggtg cgatgcgagg gcccctgccc ctgccccacg 750 gagcaggctgccacctccac cgccgatggc aaaccagaga cttgcaccgg 800 tcaggacctg gctgacctgggagatcggct gcgggactgg ttccagctcc 850 ttcatgagaa ctccaagcag aatggctcagccagcagtgt agccggcccg 900 gccagcgggc tggacaagag cctgggggcc agctgcaaggactccattgg 950 ctggatgttc tccaagctgg acaccagtgc tgacctcttc ctggaccaga1000 cggagctggc cgccatcaac ctggacaagt acgaggtctg catccgtccc 1050ttcttcaact cctgtgacac ctacaaggat ggccgggtct ctactgctga 1100 gtggtgcttctgcttctgga gggagaagcc cccctgcctg gcagagctgg 1150 agcgcatcca gatccaggaggccgccaaga agaagccagg catcttcatc 1200 ccgagctgcg acgaggatgg ctactaccggaagatgcagt gtgaccagag 1250 cagcggtgac tgctggcgtg tggaccagct gggcctggagctgactggca 1300 cgcgcacgca tgggagcccc gactgcgatg acatcgtggg cttctcgggg1350 gactttggaa gcggtgtcgg ctgggaggat gaggaggaga aggagacgga 1400ggaagcaggc gaggaggccg aggaggagga gggcgaggca ggcgaggctg 1450 acgacgggggctacatctgg tagacgccct caggagccgg ctgccggggg 1500 ggactcaaca gcagagctctgagcagcagc aggcaacttc gagaacggat 1550 ccagaaatgc agtcagaagg accctgctccacctgggggg actgggagtg 1600 tgagtgtgca tggcatgtgt gtggcacaga tggctgggacgggtgacagt 1650 gtgagtgcat gtgtgcatgc atgtgtgtat gtgtgtgtgt gtgtggcatg1700 cgctgacaaa tgtgtccttg atccacactg ctcctggcag agtgagtcac 1750ccaaaggccc cttcggcctc cttgtagctg ttttctttcc ttttgttgtt 1800 ggttttaaaatacattcaca cacaaataca aaaaaaaaaa aaaaaaaaaa 1850 aaaaaaaaaa aaaaaaaaaaaaaaaaaaaa aaaaaaaaaa aaaaaaaaa 1899 12 424 PRT Homo Sapien 12 Met ArgAla Pro Gly Cys Gly Arg Leu Val Leu Pro Leu Leu Leu 1 5 10 15 Leu AlaAla Ala Ala Leu Ala Glu Gly Asp Ala Lys Gly Leu Lys 20 25 30 Glu Gly GluThr Pro Gly Asn Phe Met Glu Asp Glu Gln Trp Leu 35 40 45 Ser Ser Ile SerGln Tyr Ser Gly Lys Ile Lys His Trp Asn Arg 50 55 60 Phe Arg Asp Glu ValGlu Asp Asp Tyr Ile Lys Ser Trp Glu Asp 65 70 75 Asn Gln Gln Gly Asp GluAla Leu Asp Thr Thr Lys Asp Pro Cys 80 85 90 Gln Lys Val Lys Cys Ser ArgHis Lys Val Cys Ile Ala Gln Gly 95 100 105 Tyr Gln Arg Ala Met Cys IleSer Arg Lys Lys Leu Glu His Arg 110 115 120 Ile Lys Gln Pro Thr Val LysLeu His Gly Asn Lys Asp Ser Ile 125 130 135 Cys Lys Pro Cys His Met AlaGln Leu Ala Ser Val Cys Gly Ser 140 145 150 Asp Gly His Thr Tyr Ser SerVal Cys Lys Leu Glu Gln Gln Ala 155 160 165 Cys Leu Ser Ser Lys Gln LeuAla Val Arg Cys Glu Gly Pro Cys 170 175 180 Pro Cys Pro Thr Glu Gln AlaAla Thr Ser Thr Ala Asp Gly Lys 185 190 195 Pro Glu Thr Cys Thr Gly GlnAsp Leu Ala Asp Leu Gly Asp Arg 200 205 210 Leu Arg Asp Trp Phe Gln LeuLeu His Glu Asn Ser Lys Gln Asn 215 220 225 Gly Ser Ala Ser Ser Val AlaGly Pro Ala Ser Gly Leu Asp Lys 230 235 240 Ser Leu Gly Ala Ser Cys LysAsp Ser Ile Gly Trp Met Phe Ser 245 250 255 Lys Leu Asp Thr Ser Ala AspLeu Phe Leu Asp Gln Thr Glu Leu 260 265 270 Ala Ala Ile Asn Leu Asp LysTyr Glu Val Cys Ile Arg Pro Phe 275 280 285 Phe Asn Ser Cys Asp Thr TyrLys Asp Gly Arg Val Ser Thr Ala 290 295 300 Glu Trp Cys Phe Cys Phe TrpArg Glu Lys Pro Pro Cys Leu Ala 305 310 315 Glu Leu Glu Arg Ile Gln IleGln Glu Ala Ala Lys Lys Lys Pro 320 325 330 Gly Ile Phe Ile Pro Ser CysAsp Glu Asp Gly Tyr Tyr Arg Lys 335 340 345 Met Gln Cys Asp Gln Ser SerGly Asp Cys Trp Arg Val Asp Gln 350 355 360 Leu Gly Leu Glu Leu Thr GlyThr Arg Thr His Gly Ser Pro Asp 365 370 375 Cys Asp Asp Ile Val Gly PheSer Gly Asp Phe Gly Ser Gly Val 380 385 390 Gly Trp Glu Asp Glu Glu GluLys Glu Thr Glu Glu Ala Gly Glu 395 400 405 Glu Ala Glu Glu Glu Glu GlyGlu Ala Gly Glu Ala Asp Asp Gly 410 415 420 Gly Tyr Ile Trp 13 2680 DNAHomo Sapien 13 tgcggcgacc gtcgtacacc atgggcctcc acctccgccc ctaccgtgtg 50gggctgctcc cggatggcct cctgttcctc ttgctgctgc taatgctgct 100 cgcggacccagcgctcccgg ccggacgtca ccccccagtg gtgctggtcc 150 ctggtgattt gggtaaccaactggaagcca agctggacaa gccgacagtg 200 gtgcactacc tctgctccaa gaagaccgaaagctacttca caatctggct 250 gaacctggaa ctgctgctgc ctgtcatcat tgactgctggattgacaata 300 tcaggctggt ttacaacaaa acatccaggg ccacccagtt tcctgatggt350 gtggatgtac gtgtccctgg ctttgggaag accttctcac tggagttcct 400ggaccccagc aaaagcagcg tgggttccta tttccacacc atggtggaga 450 gccttgtgggctggggctac acacggggtg aggatgtccg aggggctccc 500 tatgactggc gccgagccccaaatgaaaac gggccctact tcctggccct 550 ccgcgagatg atcgaggaga tgtaccagctgtatgggggc cccgtggtgc 600 tggttgccca cagtatgggc aacatgtaca cgctctactttctgcagcgg 650 cagccgcagg cctggaagga caagtatatc cgggccttcg tgtcactggg700 tgcgccctgg gggggcgtgg ccaagaccct gcgcgtcctg gcttcaggag 750acaacaaccg gatcccagtc atcgggcccc tgaagatccg ggagcagcag 800 cggtcagctgtctccaccag ctggctgctg ccctacaact acacatggtc 850 acctgagaag gtgttcgtgcagacacccac aatcaactac acactgcggg 900 actaccgcaa gttcttccag gacatcggctttgaagatgg ctggctcatg 950 cggcaggaca cagaagggct ggtggaagcc acgatgccacctggcgtgca 1000 gctgcactgc ctctatggta ctggcgtccc cacaccagac tccttctact1050 atgagagctt ccctgaccgt gaccctaaaa tctgctttgg tgacggcgat 1100ggtactgtga acttgaagag tgccctgcag tgccaggcct ggcagagccg 1150 ccaggagcaccaagtgttgc tgcaggagct gccaggcagc gagcacatcg 1200 agatgctggc caacgccaccaccctggcct atctgaaacg tgtgctcctt 1250 gggccctgac tcctgtgcca caggactcctgtggctcggc cgtggacctg 1300 ctgttggcct ctggggctgt catggcccac gcgttttgcaaagtttgtga 1350 ctcaccattc aaggccccga gtcttggact gtgaagcatc tgccatgggg1400 aagtgctgtt tgttatcctt tctctgtggc agtgaagaag gaagaaatga 1450gagtctagac tcaagggaca ctggatggca agaatgctgc tgatggtgga 1500 actgctgtgaccttaggact ggctccacag ggtggactgg ctgggccctg 1550 gtcccagtcc ctgcctggggccatgtgtcc ccctattcct gtgggctttt 1600 catacttgcc tactgggccc tggccccgcagccttcctat gagggatgtt 1650 actgggctgt ggtcctgtac ccagaggtcc cagggatcggctcctggccc 1700 ctcgggtgac ccttcccaca caccagccac agataggcct gccactggtc1750 atgggtagct agagctgctg gcttccctgt ggcttagctg gtggccagcc 1800tgactggctt cctgggcgag cctagtagct cctgcaggca ggggcagttt 1850 gttgcgttcttcgtggttcc caggccctgg gacatctcac tccactccta 1900 cctcccttac caccaggagcattcaagctc tggattgggc agcagatgtg 1950 cccccagtcc cgcaggctgt gttccaggggccctgatttc ctcggatgtg 2000 ctattggccc caggactgaa gctgcctccc ttcaccctgggactgtggtt 2050 ccaaggatga gagcaggggt tggagccatg gccttctggg aacctatgga2100 gaaagggaat ccaaggaagc agccaaggct gctcgcagct tccctgagct 2150gcacctcttg ctaaccccac catcacactg ccaccctgcc ctagggtctc 2200 actagtaccaagtgggtcag cacagggctg aggatggggc tcctatccac 2250 cctggccagc acccagcttagtgctgggac tagcccagaa acttgaatgg 2300 gaccctgaga gagccagggg tcccctgaggcccccctagg ggctttctgt 2350 ctgccccagg gtgctccatg gatctccctg tggcagcaggcatggagagt 2400 cagggctgcc ttcatggcag taggctctaa gtgggtgact ggccacaggc2450 cgagaaaagg gtacagcctc taggtggggt tcccaaagac gccttcaggc 2500tggactgagc tgctctccca cagggtttct gtgcagctgg attttctctg 2550 ttgcatacatgcctggcatc tgtctcccct tgttcctgag tggccccaca 2600 tggggctctg agcaggctgtatctggattc tggcaataaa agtactctgg 2650 atgctgtaaa aaaaaaaaaa aaaaaaaaaa2680 14 412 PRT Homo Sapien 14 Met Gly Leu His Leu Arg Pro Tyr Arg ValGly Leu Leu Pro Asp 1 5 10 15 Gly Leu Leu Phe Leu Leu Leu Leu Leu MetLeu Leu Ala Asp Pro 20 25 30 Ala Leu Pro Ala Gly Arg His Pro Pro Val ValLeu Val Pro Gly 35 40 45 Asp Leu Gly Asn Gln Leu Glu Ala Lys Leu Asp LysPro Thr Val 50 55 60 Val His Tyr Leu Cys Ser Lys Lys Thr Glu Ser Tyr PheThr Ile 65 70 75 Trp Leu Asn Leu Glu Leu Leu Leu Pro Val Ile Ile Asp CysTrp 80 85 90 Ile Asp Asn Ile Arg Leu Val Tyr Asn Lys Thr Ser Arg Ala Thr95 100 105 Gln Phe Pro Asp Gly Val Asp Val Arg Val Pro Gly Phe Gly Lys110 115 120 Thr Phe Ser Leu Glu Phe Leu Asp Pro Ser Lys Ser Ser Val Gly125 130 135 Ser Tyr Phe His Thr Met Val Glu Ser Leu Val Gly Trp Gly Tyr140 145 150 Thr Arg Gly Glu Asp Val Arg Gly Ala Pro Tyr Asp Trp Arg Arg155 160 165 Ala Pro Asn Glu Asn Gly Pro Tyr Phe Leu Ala Leu Arg Glu Met170 175 180 Ile Glu Glu Met Tyr Gln Leu Tyr Gly Gly Pro Val Val Leu Val185 190 195 Ala His Ser Met Gly Asn Met Tyr Thr Leu Tyr Phe Leu Gln Arg200 205 210 Gln Pro Gln Ala Trp Lys Asp Lys Tyr Ile Arg Ala Phe Val Ser215 220 225 Leu Gly Ala Pro Trp Gly Gly Val Ala Lys Thr Leu Arg Val Leu230 235 240 Ala Ser Gly Asp Asn Asn Arg Ile Pro Val Ile Gly Pro Leu Lys245 250 255 Ile Arg Glu Gln Gln Arg Ser Ala Val Ser Thr Ser Trp Leu Leu260 265 270 Pro Tyr Asn Tyr Thr Trp Ser Pro Glu Lys Val Phe Val Gln Thr275 280 285 Pro Thr Ile Asn Tyr Thr Leu Arg Asp Tyr Arg Lys Phe Phe Gln290 295 300 Asp Ile Gly Phe Glu Asp Gly Trp Leu Met Arg Gln Asp Thr Glu305 310 315 Gly Leu Val Glu Ala Thr Met Pro Pro Gly Val Gln Leu His Cys320 325 330 Leu Tyr Gly Thr Gly Val Pro Thr Pro Asp Ser Phe Tyr Tyr Glu335 340 345 Ser Phe Pro Asp Arg Asp Pro Lys Ile Cys Phe Gly Asp Gly Asp350 355 360 Gly Thr Val Asn Leu Lys Ser Ala Leu Gln Cys Gln Ala Trp Gln365 370 375 Ser Arg Gln Glu His Gln Val Leu Leu Gln Glu Leu Pro Gly Ser380 385 390 Glu His Ile Glu Met Leu Ala Asn Ala Thr Thr Leu Ala Tyr Leu395 400 405 Lys Arg Val Leu Leu Gly Pro 410 15 1371 DNA Homo Sapien 15cagagcagat aatggcaagc atggctgccg tgctcacctg ggctctggct 50 cttctttcagcgttttcggc cacccaggca cggaaaggct tctgggacta 100 cttcagccag accagcggggacaaaggcag ggtggagcag atccatcagc 150 agaagatggc tcgcgagccc gcgaccctgaaagacagcct tgagcaagac 200 ctcaacaata tgaacaagtt cctggaaaag ctgaggcctctgagtgggag 250 cgaggctcct cggctcccac aggacccggt gggcatgcgg cggcagctgc300 aggaggagtt ggaggaggtg aaggctcgcc tccagcccta catggcagag 350gcgcacgagc tggtgggctg gaatttggag ggcttgcggc agcaactgaa 400 gccctacacgatggatctga tggagcaggt ggccctgcgc gtgcaggagc 450 tgcaggagca gttgcgcgtggtgggggaag acaccaaggc ccagttgctg 500 gggggcgtgg acgaggcttg ggctttgctgcagggactgc agagccgcgt 550 ggtgcaccac accggccgct tcaaagagct cttccacccatacgccgaga 600 gcctggtgag cggcatcggg cgccacgtgc aggagctgca ccgcagtgtg650 gctccgcacg cccccgccag ccccgcgcgc ctcagtcgct gcgtgcaggt 700gctctcccgg aagctcacgc tcaaggccaa ggccctgcac gcacgcatcc 750 agcagaacctggaccagctg cgcgaagagc tcagcagagc ctttgcaggc 800 actgggactg aggaaggggccggcccggac ccctagatgc tctccgagga 850 ggtgcgccag cgacttcagg ctttccgccaggacacctac ctgcagatag 900 ctgccttcac tcgcgccatc gaccaggaga ctgaggaggtccagcagcag 950 ctggcgccac ctccaccagg ccacagtgcc ttcgccccag agtttcaaca1000 aacagacagt ggcaaggttc tgagcaagct gcaggcccgt ctggatgacc 1050tgtgggaaga catcactcac agccttcatg accagggcca cagccatctg 1100 ggggacccctgaggatctac ctgcccaggc ccattcccag cttcttgtct 1150 ggggagcctt ggctctgagcctctagcatg gttcagtcct tgaaagtggc 1200 ctgttgggtg gagggtggaa ggtcctgtgcaggacaggga ggccaccaaa 1250 ggggctgctg tctcctgcat atccagcctc ctgcgactccccaatctgga 1300 tgcattacat tcaccaggct ttgcaaaaaa aaaaaaaaaa aaaaaaaaaa1350 aaaaaaaaaa aaaaaaaaaa a 1371 16 274 PRT Homo Sapien 16 Met Ala SerMet Ala Ala Val Leu Thr Trp Ala Leu Ala Leu Leu 1 5 10 15 Ser Ala PheSer Ala Thr Gln Ala Arg Lys Gly Phe Trp Asp Tyr 20 25 30 Phe Ser Gln ThrSer Gly Asp Lys Gly Arg Val Glu Gln Ile His 35 40 45 Gln Gln Lys Met AlaArg Glu Pro Ala Thr Leu Lys Asp Ser Leu 50 55 60 Glu Gln Asp Leu Asn AsnMet Asn Lys Phe Leu Glu Lys Leu Arg 65 70 75 Pro Leu Ser Gly Ser Glu AlaPro Arg Leu Pro Gln Asp Pro Val 80 85 90 Gly Met Arg Arg Gln Leu Gln GluGlu Leu Glu Glu Val Lys Ala 95 100 105 Arg Leu Gln Pro Tyr Met Ala GluAla His Glu Leu Val Gly Trp 110 115 120 Asn Leu Glu Gly Leu Arg Gln GlnLeu Lys Pro Tyr Thr Met Asp 125 130 135 Leu Met Glu Gln Val Ala Leu ArgVal Gln Glu Leu Gln Glu Gln 140 145 150 Leu Arg Val Val Gly Glu Asp ThrLys Ala Gln Leu Leu Gly Gly 155 160 165 Val Asp Glu Ala Trp Ala Leu LeuGln Gly Leu Gln Ser Arg Val 170 175 180 Val His His Thr Gly Arg Phe LysGlu Leu Phe His Pro Tyr Ala 185 190 195 Glu Ser Leu Val Ser Gly Ile GlyArg His Val Gln Glu Leu His 200 205 210 Arg Ser Val Ala Pro His Ala ProAla Ser Pro Ala Arg Leu Ser 215 220 225 Arg Cys Val Gln Val Leu Ser ArgLys Leu Thr Leu Lys Ala Lys 230 235 240 Ala Leu His Ala Arg Ile Gln GlnAsn Leu Asp Gln Leu Arg Glu 245 250 255 Glu Leu Ser Arg Ala Phe Ala GlyThr Gly Thr Glu Glu Gly Ala 260 265 270 Gly Pro Asp Pro 17 2854 DNA HomoSapien 17 ctaagaggac aagatgaggc ccggcctctc atttctccta gcccttctgt 50tcttccttgg ccaagctgca ggggatttgg gggatgtggg acctccaatt 100 cccagccccggcttcagctc tttcccaggt gttgactcca gctccagctt 150 cagctccagc tccaggtcgggctccagctc cagccgcagc ttaggcagcg 200 gaggttctgt gtcccagttg ttttccaatttcaccggctc cgtggatgac 250 cgtgggacct gccagtgctc tgtttccctg ccagacaccacctttcccgt 300 ggacagagtg gaacgcttgg aattcacagc tcatgttctt tctcagaagt350 ttgagaaaga actttctaaa gtgagggaat atgtccaatt aattagtgtg 400tatgaaaaga aactgttaaa cctaactgtc cgaattgaca tcatggagaa 450 ggataccatttcttacactg aactggactt cgagctgatc aaggtagaag 500 tgaaggagat ggaaaaactggtcatacagc tgaaggagag ttttggtgga 550 agctcagaaa ttgttgacca gctggaggtggagataagaa atatgactct 600 cttggtagag aagcttgaga cactagacaa aaacaatgtccttgccattc 650 gccgagaaat cgtggctctg aagaccaagc tgaaagagtg tgaggcctct700 aaagatcaaa acacccctgt cgtccaccct cctcccactc cagggagctg 750tggtcatggt ggtgtggtga acatcagcaa accgtctgtg gttcagctca 800 actggagagggttttcttat ctatatggtg cttggggtag ggattactct 850 ccccagcatc caaacaaaggactgtattgg gtggcgccat tgaatacaga 900 tgggagactg ttggagtatt atagactgtacaacacactg gatgatttgc 950 tattgtatat aaatgctcga gagttgcgga tcacctatggccaaggtagt 1000 ggtacagcag tttacaacaa caacatgtac gtcaacatgt acaacaccgg1050 gaatattgcc agagttaacc tgaccaccaa cacgattgct gtgactcaaa 1100ctctccctaa tgctgcctat aataaccgct tttcatatgc taatgttgct 1150 tggcaagatattgactttgc tgtggatgag aatggattgt gggttattta 1200 ttcaactgaa gccagcactggtaacatggt gattagtaaa ctcaatgaca 1250 ccacacttca ggtgctaaac acttggtataccaagcagta taaaccatct 1300 gcttctaacg ccttcatggt atgtggggtt ctgtatgccacccgtactat 1350 gaacaccaga acagaagaga ttttttacta ttatgacaca aacacaggga1400 aagagggcaa actagacatt gtaatgcata agatgcagga aaaagtgcag 1450agcattaact ataacccttt tgaccagaaa ctttatgtct ataacgatgg 1500 ttaccttctgaattatgatc tttctgtctt gcagaagccc cagtaagctg 1550 tttaggagtt agggtgaaagagaaaatgtt tgttgaaaaa atagtcttct 1600 ccacttactt agatatctgc aggggtgtctaaaagtgtgt tcattttgca 1650 gcaatgttta ggtgcatagt tctaccacac tagagatctaggacatttgt 1700 cttgatttgg tgagttctct tgggaatcat ctgcctcttc aggcgcattt1750 tgcaataaag tctgtctagg gtgggattgt cagaggtcta ggggcactgt 1800gggcctagtg aagcctactg tgaggaggct tcactagaag ccttaaatta 1850 ggaattaaggaacttaaaac tcagtatggc gtctagggat tctttgtaca 1900 ggaaatattg cccaatgactagtcctcatc catgtagcac cactaattct 1950 tccatgcctg gaagaaacct ggggacttagttaggtagat taatatctgg 2000 agctcctcga gggaccaaat ctccaacttt tttttcccctcactagcacc 2050 tggaatgatg ctttgtatgt ggcagataag taaatttggc atgcttatat2100 attctacatc tgtaaagtgc tgagttttat ggagagaggc ctttttatgc 2150attaaattgt acatggcaaa taaatcccag aaggatctgt agatgaggca 2200 cctgctttttcttttctctc attgtccacc ttactaaaag tcagtagaat 2250 cttctacctc ataacttccttccaaaggca gctcagaaga ttagaaccag 2300 acttactaac caattccacc ccccaccaacccccttctac tgcctacttt 2350 aaaaaaatta atagttttct atggaactga tctaagattagaaaaattaa 2400 ttttctttaa tttcattatg gacttttatt tacatgactc taagactata2450 agaaaatctg atggcagtga caaagtgcta gcatttattg ttatctaata 2500aagaccttgg agcatatgtg caacttatga gtgtatcagt tgttgcatgt 2550 aatttttgcctttgtttaag cctggaactt gtaagaaaat gaaaatttaa 2600 tttttttttc taggacgagctatagaaaag ctattgagag tatctagtta 2650 atcagtgcag tagttggaaa ccttgctggtgtatgtgatg tgcttctgtg 2700 cttttgaatg actttatcat ctagtctttg tctatttttcctttgatgtt 2750 caagtcctag tctataggat tggcagttta aatgctttac tccccctttt2800 aaaataaatg attaaaatgt gctttgaaaa aaaaaaaaaa aaaaaaaaaa 2850 aaaa2854 18 510 PRT Homo Sapien 18 Met Arg Pro Gly Leu Ser Phe Leu Leu AlaLeu Leu Phe Phe Leu 1 5 10 15 Gly Gln Ala Ala Gly Asp Leu Gly Asp ValGly Pro Pro Ile Pro 20 25 30 Ser Pro Gly Phe Ser Ser Phe Pro Gly Val AspSer Ser Ser Ser 35 40 45 Phe Ser Ser Ser Ser Arg Ser Gly Ser Ser Ser SerArg Ser Leu 50 55 60 Gly Ser Gly Gly Ser Val Ser Gln Leu Phe Ser Asn PheThr Gly 65 70 75 Ser Val Asp Asp Arg Gly Thr Cys Gln Cys Ser Val Ser LeuPro 80 85 90 Asp Thr Thr Phe Pro Val Asp Arg Val Glu Arg Leu Glu Phe Thr95 100 105 Ala His Val Leu Ser Gln Lys Phe Glu Lys Glu Leu Ser Lys Val110 115 120 Arg Glu Tyr Val Gln Leu Ile Ser Val Tyr Glu Lys Lys Leu Leu125 130 135 Asn Leu Thr Val Arg Ile Asp Ile Met Glu Lys Asp Thr Ile Ser140 145 150 Tyr Thr Glu Leu Asp Phe Glu Leu Ile Lys Val Glu Val Lys Glu155 160 165 Met Glu Lys Leu Val Ile Gln Leu Lys Glu Ser Phe Gly Gly Ser170 175 180 Ser Glu Ile Val Asp Gln Leu Glu Val Glu Ile Arg Asn Met Thr185 190 195 Leu Leu Val Glu Lys Leu Glu Thr Leu Asp Lys Asn Asn Val Leu200 205 210 Ala Ile Arg Arg Glu Ile Val Ala Leu Lys Thr Lys Leu Lys Glu215 220 225 Cys Glu Ala Ser Lys Asp Gln Asn Thr Pro Val Val His Pro Pro230 235 240 Pro Thr Pro Gly Ser Cys Gly His Gly Gly Val Val Asn Ile Ser245 250 255 Lys Pro Ser Val Val Gln Leu Asn Trp Arg Gly Phe Ser Tyr Leu260 265 270 Tyr Gly Ala Trp Gly Arg Asp Tyr Ser Pro Gln His Pro Asn Lys275 280 285 Gly Leu Tyr Trp Val Ala Pro Leu Asn Thr Asp Gly Arg Leu Leu290 295 300 Glu Tyr Tyr Arg Leu Tyr Asn Thr Leu Asp Asp Leu Leu Leu Tyr305 310 315 Ile Asn Ala Arg Glu Leu Arg Ile Thr Tyr Gly Gln Gly Ser Gly320 325 330 Thr Ala Val Tyr Asn Asn Asn Met Tyr Val Asn Met Tyr Asn Thr335 340 345 Gly Asn Ile Ala Arg Val Asn Leu Thr Thr Asn Thr Ile Ala Val350 355 360 Thr Gln Thr Leu Pro Asn Ala Ala Tyr Asn Asn Arg Phe Ser Tyr365 370 375 Ala Asn Val Ala Trp Gln Asp Ile Asp Phe Ala Val Asp Glu Asn380 385 390 Gly Leu Trp Val Ile Tyr Ser Thr Glu Ala Ser Thr Gly Asn Met395 400 405 Val Ile Ser Lys Leu Asn Asp Thr Thr Leu Gln Val Leu Asn Thr410 415 420 Trp Tyr Thr Lys Gln Tyr Lys Pro Ser Ala Ser Asn Ala Phe Met425 430 435 Val Cys Gly Val Leu Tyr Ala Thr Arg Thr Met Asn Thr Arg Thr440 445 450 Glu Glu Ile Phe Tyr Tyr Tyr Asp Thr Asn Thr Gly Lys Glu Gly455 460 465 Lys Leu Asp Ile Val Met His Lys Met Gln Glu Lys Val Gln Ser470 475 480 Ile Asn Tyr Asn Pro Phe Asp Gln Lys Leu Tyr Val Tyr Asn Asp485 490 495 Gly Tyr Leu Leu Asn Tyr Asp Leu Ser Val Leu Gln Lys Pro Gln500 505 510 19 663 DNA Homo Sapien 19 gcaccgcaga cggcgcggat cgcagggagccggtccgccg ccggaacggg 50 agcctgggtg tgcgtgtgga gtccggactc gtgggagacgatcgcgatga 100 acacggtgct gtcgcgggcg aactcactgt tcgccttctc gctgagcgtg150 atggcggcgc tcaccttcgg ctgcttcatc accaccgcct tcaaagacag 200gagcgtcccg gtgcggctgc acgtctcgcg gatcatgcta aaaaatgtag 250 aagatttcactggacctaga gaaagaagtg atctgggatt tatcacattt 300 gatataactg ctgatctagagaatatattt gattggaatg ttaagcagtt 350 gtttctttat ttatcagcag aatattcaacaaaaaataat gctctgaacc 400 aagttgtcct atgggacaag attgttttga gaggtgataatccgaagctg 450 ctgctgaaag atatgaaaac aaaatatttt ttctttgacg atggaaatgg500 tctcaaggga aacaggaatg tcactttgac cctgtcttgg aacgtcgtac 550caaatgctgg aattctacct cttgtgacag gatcaggaca cgtatctgtc 600 ccatttccagatacatatga aataacgaag agttattaaa ttattctgaa 650 tttgaaacaa aaa 663 20180 PRT Homo Sapien 20 Met Asn Thr Val Leu Ser Arg Ala Asn Ser Leu PheAla Phe Ser 1 5 10 15 Leu Ser Val Met Ala Ala Leu Thr Phe Gly Cys PheIle Thr Thr 20 25 30 Ala Phe Lys Asp Arg Ser Val Pro Val Arg Leu His ValSer Arg 35 40 45 Ile Met Leu Lys Asn Val Glu Asp Phe Thr Gly Pro Arg GluArg 50 55 60 Ser Asp Leu Gly Phe Ile Thr Phe Asp Ile Thr Ala Asp Leu Glu65 70 75 Asn Ile Phe Asp Trp Asn Val Lys Gln Leu Phe Leu Tyr Leu Ser 8085 90 Ala Glu Tyr Ser Thr Lys Asn Asn Ala Leu Asn Gln Val Val Leu 95 100105 Trp Asp Lys Ile Val Leu Arg Gly Asp Asn Pro Lys Leu Leu Leu 110 115120 Lys Asp Met Lys Thr Lys Tyr Phe Phe Phe Asp Asp Gly Asn Gly 125 130135 Leu Lys Gly Asn Arg Asn Val Thr Leu Thr Leu Ser Trp Asn Val 140 145150 Val Pro Asn Ala Gly Ile Leu Pro Leu Val Thr Gly Ser Gly His 155 160165 Val Ser Val Pro Phe Pro Asp Thr Tyr Glu Ile Thr Lys Ser Tyr 170 175180 21 415 DNA Homo Sapien 21 aaacttgacg ccatgaagat cccggtccttcctgccgtgg tgctcctctc 50 cctcctggtg ctccactctg cccagggagc caccctgggtggtcctgagg 100 aagaaagcac cattgagaat tatgcgtcac gacccgaggc ctttaacacc150 ccgttcctga acatcgacaa attgcgatct gcgtttaagg ctgatgagtt 200cctgaactgg cacgccctct ttgagtctat caaaaggaaa cttcctttcc 250 tcaactgggatgcctttcct aagctgaaag gactgaggag cgcaactcct 300 gatgcccagt gaccatgacctccactggaa gagggggcta gcgtgagcgc 350 tgattctcaa cctaccataa ctctttcctgcctcaggaac tccaataaaa 400 cattttccat ccaaa 415 22 99 PRT Homo Sapien 22Met Lys Ile Pro Val Leu Pro Ala Val Val Leu Leu Ser Leu Leu 1 5 10 15Val Leu His Ser Ala Gln Gly Ala Thr Leu Gly Gly Pro Glu Glu 20 25 30 GluSer Thr Ile Glu Asn Tyr Ala Ser Arg Pro Glu Ala Phe Asn 35 40 45 Thr ProPhe Leu Asn Ile Asp Lys Leu Arg Ser Ala Phe Lys Ala 50 55 60 Asp Glu PheLeu Asn Trp His Ala Leu Phe Glu Ser Ile Lys Arg 65 70 75 Lys Leu Pro PheLeu Asn Trp Asp Ala Phe Pro Lys Leu Lys Gly 80 85 90 Leu Arg Ser Ala ThrPro Asp Ala Gln 95 23 866 DNA Homo Sapien 23 tctcagactc ttggaaggggctatactaga cacacaaaga cagccccaag 50 aaggacggtg gagtagtgtc ctcgctaaaagacagtagat atgcaacgcc 100 tcttgctcct gccctttctc ctgctgggaa cagtttctgctcttcatctg 150 gagaatgatg ccccccatct ggagagccta gagacacagg cagacctagg200 ccaggatctg gatagttcaa aggagcagga gagagacttg gctctgacgg 250aggaggtgat tcaggcagag ggagaggagg tcaaggcttc tgcctgtcaa 300 gacaactttgaggatgagga agccatggag tcggacccag ctgccttaga 350 caaggacttc cagtgccccagggaagaaga cattgttgaa gtgcagggaa 400 gtccaaggtg caagacctgc cgctacctattggtgcggac tcctaaaact 450 tttgcagaag ctcagaatgt ctgcagcaga tgctacggaggcaaccttgt 500 ctctatccat gacttcaact tcaactatcg cattcagtgc tgcactagca550 cagtcaacca agcccaggtc tggattggag gcaacctcag gggctggttc 600ctgtggaagc ggttttgctg gactgatggg agccactgga attttgctta 650 ctggtccccagggcaacctg ggaatgggca aggctcctgt gtggccctat 700 gcaccaaagg aggttattggcgacgagctc aatgcgacaa gcaactgccc 750 ttcgtctgct ccttctaagc cagcggcacggagaccctgc cagcagctcc 800 ctcccgtccc ccaacctctc ctgctcataa atccagacttcccacagcaa 850 aaaaaaaaaa aaaaaa 866 24 225 PRT Homo Sapien 24 Met GlnArg Leu Leu Leu Leu Pro Phe Leu Leu Leu Gly Thr Val 1 5 10 15 Ser AlaLeu His Leu Glu Asn Asp Ala Pro His Leu Glu Ser Leu 20 25 30 Glu Thr GlnAla Asp Leu Gly Gln Asp Leu Asp Ser Ser Lys Glu 35 40 45 Gln Glu Arg AspLeu Ala Leu Thr Glu Glu Val Ile Gln Ala Glu 50 55 60 Gly Glu Glu Val LysAla Ser Ala Cys Gln Asp Asn Phe Glu Asp 65 70 75 Glu Glu Ala Met Glu SerAsp Pro Ala Ala Leu Asp Lys Asp Phe 80 85 90 Gln Cys Pro Arg Glu Glu AspIle Val Glu Val Gln Gly Ser Pro 95 100 105 Arg Cys Lys Thr Cys Arg TyrLeu Leu Val Arg Thr Pro Lys Thr 110 115 120 Phe Ala Glu Ala Gln Asn ValCys Ser Arg Cys Tyr Gly Gly Asn 125 130 135 Leu Val Ser Ile His Asp PheAsn Phe Asn Tyr Arg Ile Gln Cys 140 145 150 Cys Thr Ser Thr Val Asn GlnAla Gln Val Trp Ile Gly Gly Asn 155 160 165 Leu Arg Gly Trp Phe Leu TrpLys Arg Phe Cys Trp Thr Asp Gly 170 175 180 Ser His Trp Asn Phe Ala TyrTrp Ser Pro Gly Gln Pro Gly Asn 185 190 195 Gly Gln Gly Ser Cys Val AlaLeu Cys Thr Lys Gly Gly Tyr Trp 200 205 210 Arg Arg Ala Gln Cys Asp LysGln Leu Pro Phe Val Cys Ser Phe 215 220 225 25 584 DNA Homo Sapien 25caacagaagc caagaaggaa gccgtctatc ttgtggcgat catgtataag 50 ctggcctcctgctgtttgct tttcacagga ttcttaaatc ctctcttatc 100 tcttcctctc cttgactccagggaaatatc ctttcaactc tcagcacctc 150 atgaagacgc gcgcttaact ccggaggagctagaaagagc ttcccttcta 200 cagatattgc cagagatgct gggtgcagaa agaggggatattctcaggaa 250 agcagactca agtaccaaca tttttaaccc aagaggaaat ttgagaaagt300 ttcaggattt ctctggacaa gatcctaaca ttttactgag tcatcttttg 350gccagaatct ggaaaccata caagaaacgt gagactcctg attgcttctg 400 gaaatactgtgtctgaagtg aaataagcat ctgttagtca gctcagaaac 450 acccatctta gaatatgaaaaataacacaa tgcttgattt gaaaacagtg 500 tggagaaaaa ctaggcaaac tacaccctgttcattgttac ctggaaaata 550 aatcctctat gttttgcaca aaaaaaaaaa aaaa 584 26124 PRT Homo Sapien 26 Met Tyr Lys Leu Ala Ser Cys Cys Leu Leu Phe ThrGly Phe Leu 1 5 10 15 Asn Pro Leu Leu Ser Leu Pro Leu Leu Asp Ser ArgGlu Ile Ser 20 25 30 Phe Gln Leu Ser Ala Pro His Glu Asp Ala Arg Leu ThrPro Glu 35 40 45 Glu Leu Glu Arg Ala Ser Leu Leu Gln Ile Leu Pro Glu MetLeu 50 55 60 Gly Ala Glu Arg Gly Asp Ile Leu Arg Lys Ala Asp Ser Ser Thr65 70 75 Asn Ile Phe Asn Pro Arg Gly Asn Leu Arg Lys Phe Gln Asp Phe 8085 90 Ser Gly Gln Asp Pro Asn Ile Leu Leu Ser His Leu Leu Ala Arg 95 100105 Ile Trp Lys Pro Tyr Lys Lys Arg Glu Thr Pro Asp Cys Phe Trp 110 115120 Lys Tyr Cys Val 27 920 DNA Homo Sapien 27 caagtaaatg cagcactagtgggtgggatt gaggtatgcc ctggtgcata 50 aatagagact cagctgtgct ggcacactcagaagcttgga ccgcatccta 100 gccgccgact cacacaaggc aggtgggtga ggaaatccagagttgccatg 150 gagaaaattc cagtgtcagc attcttgctc cttgtggccc tctcctacac200 tctggccaga gataccacag tcaaacctgg agccaaaaag gacacaaagg 250actctcgacc caaactgccc cagaccctct ccagaggttg gggtgaccaa 300 ctcatctggactcagacata tgaagaagct ctatataaat ccaagacaag 350 caacaaaccc ttgatgattattcatcactt ggatgagtgc ccacacagtc 400 aagctttaaa gaaagtgttt gctgaaaataaagaaatcca gaaattggca 450 gagcagtttg tcctcctcaa tctggtttat gaaacaactgacaaacacct 500 ttctcctgat ggccagtatg tccccaggat tatgtttgtt gacccatctc550 tgacagttag agccgatatc actggaagat attcaaatcg tctctatgct 600tacgaacctg cagatacagc tctgttgctt gacaacatga agaaagctct 650 caagttgctgaagactgaat tgtaaagaaa aaaaatctcc aagcccttct 700 gtctgtcagg ccttgagacttgaaaccaga agaagtgtga gaagactggc 750 tagtgtggaa gcatagtgaa cacactgattaggttatggt ttaatgttac 800 aacaactatt ttttaagaaa aacaagtttt agaaatttggtttcaagtgt 850 acatgtgtga aaacaatatt gtatactacc atagtgagcc atgattttct900 aaaaaaaaaa ataaatgtta 920 28 175 PRT Homo Sapien 28 Met Glu Lys IlePro Val Ser Ala Phe Leu Leu Leu Val Ala Leu 1 5 10 15 Ser Tyr Thr LeuAla Arg Asp Thr Thr Val Lys Pro Gly Ala Lys 20 25 30 Lys Asp Thr Lys AspSer Arg Pro Lys Leu Pro Gln Thr Leu Ser 35 40 45 Arg Gly Trp Gly Asp GlnLeu Ile Trp Thr Gln Thr Tyr Glu Glu 50 55 60 Ala Leu Tyr Lys Ser Lys ThrSer Asn Lys Pro Leu Met Ile Ile 65 70 75 His His Leu Asp Glu Cys Pro HisSer Gln Ala Leu Lys Lys Val 80 85 90 Phe Ala Glu Asn Lys Glu Ile Gln LysLeu Ala Glu Gln Phe Val 95 100 105 Leu Leu Asn Leu Val Tyr Glu Thr ThrAsp Lys His Leu Ser Pro 110 115 120 Asp Gly Gln Tyr Val Pro Arg Ile MetPhe Val Asp Pro Ser Leu 125 130 135 Thr Val Arg Ala Asp Ile Thr Gly ArgTyr Ser Asn Arg Leu Tyr 140 145 150 Ala Tyr Glu Pro Ala Asp Thr Ala LeuLeu Leu Asp Asn Met Lys 155 160 165 Lys Ala Leu Lys Leu Leu Lys Thr GluLeu 170 175 29 1181 DNA Homo Sapien 29 aagaccctct ctttcgctgt ttgagagtctctcggctcaa ggaccgggag 50 gtaagaggtt tgggactgcc ccggcaactc cagggtgtctggtccacgac 100 ctatcctagg cgccatgggt gtgataggta tacagctggt tgttaccatg150 gtgatggcca gtgtcatgca gaagattata cctcactatt ctcttgctcg 200atggctactc tgtaatggca gtttgaggtg gtatcaacat cctacagaag 250 aagaattaagaattcttgca gggaaacaac aaaaagggaa aaccaaaaaa 300 gataggaaat ataatggtcacattgaaagt aagccattaa ccattccaaa 350 ggatattgac cttcatctag aaacaaagtcagttacagaa gtggatactt 400 tagcattgca ttactttcca gaataccagt ggctggtggatttcacagtg 450 gctgctacag ttgtgtatct agtaactgaa gtctactaca attttatgaa500 gcctacacag gaaatgaata tcagcttagt ctggtgccta cttgttttgt 550cttttgcaat caaagttcta ttttcattaa ctacacacta ttttaaagta 600 gaagatggtggtgaaagatc tgtttgtgtc acctttggat tttttttctt 650 tgtcaaagca atggcagtgttgattgtaac agaaaattat ctggaatttg 700 gacttgaaac agggtttaca aatttttcagacagtgcgat gcagtttctt 750 gaaaagcaag gtttagaatc tcagagtcct gtttcaaaacttactttcaa 800 atttttcctg gctattttct gttcattcat tggggctttt ttgacatttc850 ctggattacg actggctcaa atgcatctgg atgccctgaa tttggcaaca 900gaaaaaatta cacaaacttt acttcatatc aacttcttgg cacctttatt 950 tatggttttgctctgggtaa aaccaatcac caaagactac attatgaacc 1000 caccactggg caaagaaatttccccatctg gaagatgaag ataatagtat 1050 ctaactcaca aggttatcat tggaataaatgaaagaacac atgtaatgca 1100 accagctgga attaagtgct taataaatgt tcttttcactgctttgcctc 1150 atcagaatta aaatagaaat acttgactag t 1181 30 307 PRT HomoSapien 30 Met Gly Val Ile Gly Ile Gln Leu Val Val Thr Met Val Met Ala 15 10 15 Ser Val Met Gln Lys Ile Ile Pro His Tyr Ser Leu Ala Arg Trp 2025 30 Leu Leu Cys Asn Gly Ser Leu Arg Trp Tyr Gln His Pro Thr Glu 35 4045 Glu Glu Leu Arg Ile Leu Ala Gly Lys Gln Gln Lys Gly Lys Thr 50 55 60Lys Lys Asp Arg Lys Tyr Asn Gly His Ile Glu Ser Lys Pro Leu 65 70 75 ThrIle Pro Lys Asp Ile Asp Leu His Leu Glu Thr Lys Ser Val 80 85 90 Thr GluVal Asp Thr Leu Ala Leu His Tyr Phe Pro Glu Tyr Gln 95 100 105 Trp LeuVal Asp Phe Thr Val Ala Ala Thr Val Val Tyr Leu Val 110 115 120 Thr GluVal Tyr Tyr Asn Phe Met Lys Pro Thr Gln Glu Met Asn 125 130 135 Ile SerLeu Val Trp Cys Leu Leu Val Leu Ser Phe Ala Ile Lys 140 145 150 Val LeuPhe Ser Leu Thr Thr His Tyr Phe Lys Val Glu Asp Gly 155 160 165 Gly GluArg Ser Val Cys Val Thr Phe Gly Phe Phe Phe Phe Val 170 175 180 Lys AlaMet Ala Val Leu Ile Val Thr Glu Asn Tyr Leu Glu Phe 185 190 195 Gly LeuGlu Thr Gly Phe Thr Asn Phe Ser Asp Ser Ala Met Gln 200 205 210 Phe LeuGlu Lys Gln Gly Leu Glu Ser Gln Ser Pro Val Ser Lys 215 220 225 Leu ThrPhe Lys Phe Phe Leu Ala Ile Phe Cys Ser Phe Ile Gly 230 235 240 Ala PheLeu Thr Phe Pro Gly Leu Arg Leu Ala Gln Met His Leu 245 250 255 Asp AlaLeu Asn Leu Ala Thr Glu Lys Ile Thr Gln Thr Leu Leu 260 265 270 His IleAsn Phe Leu Ala Pro Leu Phe Met Val Leu Leu Trp Val 275 280 285 Lys ProIle Thr Lys Asp Tyr Ile Met Asn Pro Pro Leu Gly Lys 290 295 300 Glu IleSer Pro Ser Gly Arg 305 31 513 DNA Homo Sapien 31 gtagcatagt gtgcagttcactggaccaaa agctttggct gcacctcttc 50 tggaaagctg gccatggggc tcttcatgatcattgcaatt ctgctgttcc 100 agaaacccac agtaaccgaa caacttaaga agtgctggaataactatgta 150 caaggacatt gcaggaaaat ctgcagagta aatgaagtgc ctgaggcact200 atgtgaaaat gggagatact gttgcctcaa tatcaaggaa ctggaagcat 250gtaaaaaaat tacaaagcca cctcgtccaa agccagcaac acttgcactg 300 actcttcaagactatgttac aataatagaa aatttcccaa gcctgaagac 350 acagtctaca taaatcaaatacaatttcgt tttcacttgc ttctcaacct 400 agtctaataa actaaggtga tgagatatacatcttcttcc ttctggtttc 450 ttgatcctta aaatgacctt cgagcatatt ctaataaagtgcattgccag 500 ttaaaaaaaa aaa 513 32 99 PRT Homo Sapien 32 Met Gly LeuPhe Met Ile Ile Ala Ile Leu Leu Phe Gln Lys Pro 1 5 10 15 Thr Val ThrGlu Gln Leu Lys Lys Cys Trp Asn Asn Tyr Val Gln 20 25 30 Gly His Cys ArgLys Ile Cys Arg Val Asn Glu Val Pro Glu Ala 35 40 45 Leu Cys Glu Asn GlyArg Tyr Cys Cys Leu Asn Ile Lys Glu Leu 50 55 60 Glu Ala Cys Lys Lys IleThr Lys Pro Pro Arg Pro Lys Pro Ala 65 70 75 Thr Leu Ala Leu Thr Leu GlnAsp Tyr Val Thr Ile Ile Glu Asn 80 85 90 Phe Pro Ser Leu Lys Thr Gln SerThr 95 33 2684 DNA Homo Sapien unsure 2636-2637 unknown base 33cggacgcgtg ggcgctgagc cccggaggcc agggcgtccg gggctgcgcc 50 acttccgagggccgagcgct gccggtcccg gcggtgcgac acggccggga 100 ggaggagaac aacgcaaggggctcaaccgt cggtcgctgg agcccccccc 150 ggggcgtggc ctcccgcccc ctcagctggggagggcgggg ctcgctgccc 200 cctgctgccg actgcgaccc ttacagggga gggagggcgcaggccgcgcg 250 gagatgagga ggaggctgcg cctacgcagg gacgcattgc tcacgctgct300 ccttggcgcc tccctgggcc tcttactcta tgcgcagcgc gacggcgcgg 350ccccgacggc gagcgcgccg cgagggcgag ggagggcggc accgaggccc 400 acccccggaccccgcgcgtt ccagttaccc gacgcgggtg cagccccgcc 450 ggcctacgaa ggggacacaccggcgccgcc cacgcctacg ggaccctttg 500 acttcgcccg ctatttgcgc gccaaggaccagcggcggtt tccactgctc 550 attaaccagc cgcacaagtg ccgcggcgac ggcgcacccggtggccgccc 600 ggacctgctt attgctgtca agtcggtggc agaggacttc gagcggcgcc650 aagccgtgcg ccagacgtgg ggcgcggagg gtcgcgtgca gggggcgctg 700gtgcgccgcg tgttcttgct gggcgtgccc aggggcgcag gctcgggcgg 750 ggccgacgaagttggggagg gcgcgcgaac ccactggcgc gccctgctgc 800 gggccgagag ccttgcgtatgcggacatcc tgctctgggc cttcgacgac 850 acctttttta acctaacgct caaggagatccactttctag cctgggcctc 900 agctttctgc cccgacgtgc gcttcgtttt taagggcgacgcagatgtgt 950 tcgtgaacgt gggaaatctc ctggagttcc tggcgccgcg ggacccggcg1000 caagacctgc ttgctggtga cgtaattgtg catgcgcggc ccatccgcac 1050gcgggctagc aagtactaca tccccgaggc cgtgtacggc ctgcccgcct 1100 atccggcctacgcgggcggc ggtggctttg tgctttccgg ggccacgctg 1150 caccgcctgg ctggcgcctgtgcgcaggtc gagctcttcc ccatcgacga 1200 cgtctttctg ggcatgtgtc tgcagcgcctgcggctcacg cccgagcctc 1250 accctgcctt ccgcaccttt ggcatccccc agccttcagccgcgccgcat 1300 ttgagcacct tcgacccctg cttttaccgt gagctggttg tagtgcacgg1350 gctctcggcc gctgacatct ggcttatgtg gcgcctgctg cacgggccgc 1400atgggccagc ctgtgcgcat ccacagcctg tcgctgcagg ccccttccaa 1450 tgggactcctagctccccac tacagcccca agctcctaac tcagacccag 1500 aatggagccg gtttcccagattattgccgt gtatgtggtt cttccctgat 1550 caccaggtgc ctgtctccac aggatcccaggggatggggg ttaagcttgg 1600 ctcctggcgg tccaccctgc tggaaccagt tgaaacccgtgtaatggtga 1650 ccctttgagc gagccaaggc tgggtggtag atgaccatct cttgtccaac1700 aggtcccaga gcagtggata tgtctggtcc tcctagtagc acagaggtgt 1750gttctggtgt ggtggcaggg acttagggaa tcctaccact ctgctggatt 1800 tggaaccccctaggctgacg cggacgtatg cagaggctct caaggccagg 1850 ccccacaggg aggtggaggggctccggccg ccacagcctg aattcatgaa 1900 cctggcaggc actttgccat agctcatctgaaaacagata ttatgcttcc 1950 cacaacctct cctgggccca ggtgtggctg agcaccagggatggagccac 2000 acataaggga caaatgagtg cacggtccta cctagtcttt cctcacctcc2050 tgaactcaca caacaatgcc agtctcccac tggaggctgt atcccctcag 2100aggagccaag gaatgtcttc ccctgagatg ccaccactat taatttcccc 2150 atatgcttcaaccaccccct tgctcaaaaa accaataccc acacttacct 2200 taatacaaac atcccagcaacagcacatgg caggccattg ctgagggcac 2250 aggtgcttta ttggagaggg gatgtgggcaggggataagg aaggttcccc 2300 cattccagga ggatgggaac agtcctggct gcccctgacagtggggatat 2350 gcaaggggct ctggccaggc cacagtccaa atgggaagac accagtcagt2400 cacaaaagtc gggagcgcca cacaaacctg gctataaggc ccaggaacca 2450tataggagcc tgagacaggt cccctgcaca ttcatcatta aactatacag 2500 gatgaggctgtacatgagtt aattacaaaa gagtcatatt tacaaaaatc 2550 tgtacacaca tttgaaaaactcacaaaatt gtcatctatg tatcacaagt 2600 tgctagaccc aaaatattaa aaatgggataaaattnnttt aaaaaaaaaa 2650 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaa 2684 34402 PRT Homo Sapien 34 Met Arg Arg Arg Leu Arg Leu Arg Arg Asp Ala LeuLeu Thr Leu 1 5 10 15 Leu Leu Gly Ala Ser Leu Gly Leu Leu Leu Tyr AlaGln Arg Asp 20 25 30 Gly Ala Ala Pro Thr Ala Ser Ala Pro Arg Gly Arg GlyArg Ala 35 40 45 Ala Pro Arg Pro Thr Pro Gly Pro Arg Ala Phe Gln Leu ProAsp 50 55 60 Ala Gly Ala Ala Pro Pro Ala Tyr Glu Gly Asp Thr Pro Ala Pro65 70 75 Pro Thr Pro Thr Gly Pro Phe Asp Phe Ala Arg Tyr Leu Arg Ala 8085 90 Lys Asp Gln Arg Arg Phe Pro Leu Leu Ile Asn Gln Pro His Lys 95 100105 Cys Arg Gly Asp Gly Ala Pro Gly Gly Arg Pro Asp Leu Leu Ile 110 115120 Ala Val Lys Ser Val Ala Glu Asp Phe Glu Arg Arg Gln Ala Val 125 130135 Arg Gln Thr Trp Gly Ala Glu Gly Arg Val Gln Gly Ala Leu Val 140 145150 Arg Arg Val Phe Leu Leu Gly Val Pro Arg Gly Ala Gly Ser Gly 155 160165 Gly Ala Asp Glu Val Gly Glu Gly Ala Arg Thr His Trp Arg Ala 170 175180 Leu Leu Arg Ala Glu Ser Leu Ala Tyr Ala Asp Ile Leu Leu Trp 185 190195 Ala Phe Asp Asp Thr Phe Phe Asn Leu Thr Leu Lys Glu Ile His 200 205210 Phe Leu Ala Trp Ala Ser Ala Phe Cys Pro Asp Val Arg Phe Val 215 220225 Phe Lys Gly Asp Ala Asp Val Phe Val Asn Val Gly Asn Leu Leu 230 235240 Glu Phe Leu Ala Pro Arg Asp Pro Ala Gln Asp Leu Leu Ala Gly 245 250255 Asp Val Ile Val His Ala Arg Pro Ile Arg Thr Arg Ala Ser Lys 260 265270 Tyr Tyr Ile Pro Glu Ala Val Tyr Gly Leu Pro Ala Tyr Pro Ala 275 280285 Tyr Ala Gly Gly Gly Gly Phe Val Leu Ser Gly Ala Thr Leu His 290 295300 Arg Leu Ala Gly Ala Cys Ala Gln Val Glu Leu Phe Pro Ile Asp 305 310315 Asp Val Phe Leu Gly Met Cys Leu Gln Arg Leu Arg Leu Thr Pro 320 325330 Glu Pro His Pro Ala Phe Arg Thr Phe Gly Ile Pro Gln Pro Ser 335 340345 Ala Ala Pro His Leu Ser Thr Phe Asp Pro Cys Phe Tyr Arg Glu 350 355360 Leu Val Val Val His Gly Leu Ser Ala Ala Asp Ile Trp Leu Met 365 370375 Trp Arg Leu Leu His Gly Pro His Gly Pro Ala Cys Ala His Pro 380 385390 Gln Pro Val Ala Ala Gly Pro Phe Gln Trp Asp Ser 395 400 35 1643 DNAHomo Sapien 35 agcagcctct gcccgacccg gctcgtgcgg accccaggac cgggcgcggg 50acgcgtgcgt ccagcctccg gcgctgcgga gacccgcggc tgggtccggg 100 gaggccccaaacccgccccc gccagaaccc cgccccaaat tcccacctcc 150 tccagaagcc ccgcccactcccgagccccg agagctccgc gcacctgggc 200 gccatccgcc ctggctccgc tgcacgagctccacgcccgt accccggcgt 250 cacgctcagc ccgcggtgct cgcacacctg agactcatctcgcttcgacc 300 ccgccgccgc cgccgcccgg catcctgagc acggagacag tctccagctg350 ccgttcatgc ttcctcccca gccttccgca gcccaccagg gaaggggcgg 400taggagtggc cttttaccaa agggaccggc gatgctctgc aggctgtgct 450 ggctggtctcgtacagcttg gctgtgctgt tgctcggctg cctgctcttc 500 ctgaggaagg cggccaagcccgcaggagac cccacggccc accagccttt 550 ctgggctccc ccaacacccc gtcacagccggtgtccaccc aaccacacag 600 tgtctagcgc ctctctgtcc ctgcctagcc gtcaccgtctcttcttgacc 650 tatcgtcact gccgaaattt ctctatcttg ctggagcctt caggctgttc700 caaggatacc ttcttgctcc tggccatcaa gtcacagcct ggtcacgtgg 750agcgacgtgc ggctatccgc agcacgtggg gcagggtggg gggatgggct 800 aggggccggcagctgaagct ggtgttcctc ctaggggtgg caggatccgc 850 tcccccagcc cagctgctggcctatgagag tagggagttt gatgacatcc 900 tccagtggga cttcactgag gacttcttcaacctgacgct caaggagctg 950 cacctgcagc gctgggtggt ggctgcctgc ccccaggcccatttcatgct 1000 aaagggagat gacgatgtct ttgtccacgt ccccaacgtg ttagagttcc1050 tggatggctg ggacccagcc caggacctcc tggtgggaga tgtcatccgc 1100caagccctgc ccaacaggaa cactaaggtc aaatacttca tcccaccctc 1150 aatgtacagggccacccact acccacccta tgctggtggg ggaggatatg 1200 tcatgtccag agccacagtgcggcgcctcc aggctatcat ggaagatgct 1250 gaactcttcc ccattgatga tgtctttgtgggtatgtgcc tgaggaggct 1300 ggggctgagc cctatgcacc atgctggctt caagacatttggaatccggc 1350 ggcccctgga ccccttagac ccctgcctgt atagggggct cctgctggtt1400 caccgcctca gccccctcga gatgtggacc atgtgggcac tggtgacaga 1450tgaggggctc aagtgtgcag ctggccccat accccagcgc tgaagggtgg 1500 gttgggcaacagcctgagag tggactcagt gttgattctc tatcgtgatg 1550 cgaaattgat gcctgctgctctacagaaaa tgccaacttg gttttttaac 1600 tcctctcacc ctgttagctc tgattaaaaacactgcaacc caa 1643 36 378 PRT Homo Sapien 36 Met Leu Pro Pro Gln ProSer Ala Ala His Gln Gly Arg Gly Gly 1 5 10 15 Arg Ser Gly Leu Leu ProLys Gly Pro Ala Met Leu Cys Arg Leu 20 25 30 Cys Trp Leu Val Ser Tyr SerLeu Ala Val Leu Leu Leu Gly Cys 35 40 45 Leu Leu Phe Leu Arg Lys Ala AlaLys Pro Ala Gly Asp Pro Thr 50 55 60 Ala His Gln Pro Phe Trp Ala Pro ProThr Pro Arg His Ser Arg 65 70 75 Cys Pro Pro Asn His Thr Val Ser Ser AlaSer Leu Ser Leu Pro 80 85 90 Ser Arg His Arg Leu Phe Leu Thr Tyr Arg HisCys Arg Asn Phe 95 100 105 Ser Ile Leu Leu Glu Pro Ser Gly Cys Ser LysAsp Thr Phe Leu 110 115 120 Leu Leu Ala Ile Lys Ser Gln Pro Gly His ValGlu Arg Arg Ala 125 130 135 Ala Ile Arg Ser Thr Trp Gly Arg Val Gly GlyTrp Ala Arg Gly 140 145 150 Arg Gln Leu Lys Leu Val Phe Leu Leu Gly ValAla Gly Ser Ala 155 160 165 Pro Pro Ala Gln Leu Leu Ala Tyr Glu Ser ArgGlu Phe Asp Asp 170 175 180 Ile Leu Gln Trp Asp Phe Thr Glu Asp Phe PheAsn Leu Thr Leu 185 190 195 Lys Glu Leu His Leu Gln Arg Trp Val Val AlaAla Cys Pro Gln 200 205 210 Ala His Phe Met Leu Lys Gly Asp Asp Asp ValPhe Val His Val 215 220 225 Pro Asn Val Leu Glu Phe Leu Asp Gly Trp AspPro Ala Gln Asp 230 235 240 Leu Leu Val Gly Asp Val Ile Arg Gln Ala LeuPro Asn Arg Asn 245 250 255 Thr Lys Val Lys Tyr Phe Ile Pro Pro Ser MetTyr Arg Ala Thr 260 265 270 His Tyr Pro Pro Tyr Ala Gly Gly Gly Gly TyrVal Met Ser Arg 275 280 285 Ala Thr Val Arg Arg Leu Gln Ala Ile Met GluAsp Ala Glu Leu 290 295 300 Phe Pro Ile Asp Asp Val Phe Val Gly Met CysLeu Arg Arg Leu 305 310 315 Gly Leu Ser Pro Met His His Ala Gly Phe LysThr Phe Gly Ile 320 325 330 Arg Arg Pro Leu Asp Pro Leu Asp Pro Cys LeuTyr Arg Gly Leu 335 340 345 Leu Leu Val His Arg Leu Ser Pro Leu Glu MetTrp Thr Met Trp 350 355 360 Ala Leu Val Thr Asp Glu Gly Leu Lys Cys AlaAla Gly Pro Ile 365 370 375 Pro Gln Arg 37 1226 DNA Homo Sapien 37atgaaagtga taatcaggca gcccaaatga ttgttaataa ggatcaaatg 50 agatcgtgtatgtgggtcca atcaattgat tctacacaaa ggagcctggg 100 gaggggccat ggtgccaatgcacttactgg ggagactgga gaagccgctt 150 ctcctcctgt gctgcgcctc cttcctactggggctggctt tgctgggcat 200 aaagacggac atcacccccg ttgcttattt ctttctcacattgggtggct 250 tcttcttgtt tgcctatctc ctggtccggt ttctggaatg ggggcttcgg300 tcccagctcc aatcaatgca gactgagagc ccagggccct caggcaatgc 350acgggacaat gaagcctttg aagtgccagt ctatgaagag gccgtggtgg 400 gactagaatcccagtgccgc ccccaagagt tggaccaacc acccccctac 450 agcactgttg tgatacccccagcacctgag gaggaacaac ctagccatcc 500 agaggggtcc aggagagcca aactggaacagaggcgaatg gcctcagagg 550 ggtccatggc ccaggaagga agccctggaa gagctccaatcaaccttcgg 600 cttcggggac cacgggctgt gtccactgct cctgatctgc agagcttggc650 ggcagtcccc acattagagc ctctgactcc accccctgcc tatgatgtct 700gctttggtca ccctgatgat gatagtgttt tttatgagga caactgggca 750 cccccttaaatgactctccc aagatttctc ttctctccac accagacctc 800 gttcatttga ctaacattttccagcgccta ctatgtgtca gaaacaagtg 850 tttctgcctg gacatcataa atggggacttggaccctgag gagagtcagg 900 ccacggtaag cccttcccag ctgagatatg ggtggcataatttgagtctt 950 ctggcaacat ttggtgacct accccatatc caatatttcc agcgttagat1000 tgaggatgag gtagggaggt gatccagaga aggcggagaa ggaagaagta 1050acctctgagt ggcggctatt gcttctgttc caggtgctgt tcgagctgtt 1100 agaacccttaggcttgacag ctttgtgagt tattattgaa aaatgaggat 1150 tccaagagtc agaggagtttgataatgtgc acgagggcac actgctagta 1200 aataacatta aaataactgg aatgaa 122638 216 PRT Homo Sapien 38 Met Val Pro Met His Leu Leu Gly Arg Leu GluLys Pro Leu Leu 1 5 10 15 Leu Leu Cys Cys Ala Ser Phe Leu Leu Gly LeuAla Leu Leu Gly 20 25 30 Ile Lys Thr Asp Ile Thr Pro Val Ala Tyr Phe PheLeu Thr Leu 35 40 45 Gly Gly Phe Phe Leu Phe Ala Tyr Leu Leu Val Arg PheLeu Glu 50 55 60 Trp Gly Leu Arg Ser Gln Leu Gln Ser Met Gln Thr Glu SerPro 65 70 75 Gly Pro Ser Gly Asn Ala Arg Asp Asn Glu Ala Phe Glu Val Pro80 85 90 Val Tyr Glu Glu Ala Val Val Gly Leu Glu Ser Gln Cys Arg Pro 95100 105 Gln Glu Leu Asp Gln Pro Pro Pro Tyr Ser Thr Val Val Ile Pro 110115 120 Pro Ala Pro Glu Glu Glu Gln Pro Ser His Pro Glu Gly Ser Arg 125130 135 Arg Ala Lys Leu Glu Gln Arg Arg Met Ala Ser Glu Gly Ser Met 140145 150 Ala Gln Glu Gly Ser Pro Gly Arg Ala Pro Ile Asn Leu Arg Leu 155160 165 Arg Gly Pro Arg Ala Val Ser Thr Ala Pro Asp Leu Gln Ser Leu 170175 180 Ala Ala Val Pro Thr Leu Glu Pro Leu Thr Pro Pro Pro Ala Tyr 185190 195 Asp Val Cys Phe Gly His Pro Asp Asp Asp Ser Val Phe Tyr Glu 200205 210 Asp Asn Trp Ala Pro Pro 215 39 2770 DNA Homo Sapien 39cccacgcgtc cggcggctac acacctaggt gcggtgggct tcgggtgggg 50 ggcctgcagctagctgatgg caagggagga atagcagggg tggggattgt 100 ggtgtgcgag aggtcccgcggacggggggc tcgggggtct cttcagacga 150 gattcccttc aggcttgggc cgggtcccttcgcacggaga tcccaatgaa 200 cgcgggcccc tggaggccgg tggttggggc ttctccgcgtcggggatggg 250 gccggtaccc tagcccgttt ccagcgcctc agtcggttcc ccatgccctc300 agaggtggcc cggggcaagc gcgccgccct cttcttcgct gcggtggcca 350tcgtgctggg gctaccgctc tggtggaaga ccacggagac ctaccgggcc 400 tcgttgccttactcccagat cagtggcctg aatgcccttc agctccgcct 450 catggtgcct gtcactgtcgtgtttacgcg ggagtcagtg cccctggacg 500 accaggagaa gctgcccttc accgttgtgcatgaaagaga gattcctctg 550 aaatacaaaa tgaaaatcaa atgccgtttc cagaaggcctatcggagggc 600 tttggaccat gaggaggagg ccctgtcatc gggcagtgtg caagaggcag650 aagccatgtt agatgagcct caggaacaag cggagggctc cctgactgtg 700tacgtgatat ctgaacactc ctcacttctt ccccaggaca tgatgagcta 750 cattgggcccaagaggacag cagtggtgcg ggggataatg caccgggagg 800 cctttaacat cattggccgccgcatagtcc aggtggccca ggccatgtct 850 ttgactgagg atgtgcttgc tgctgctctggctgaccacc ttccagagga 900 caagtggagc gctgagaaga ggcggcctct caagtccagcttgggctatg 950 agatcacctt cagtttactc aacccagacc ccaagtccca tgatgtctac1000 tgggacattg agggggctgt ccggcgctat gtgcaacctt tcctgaatgc 1050cctcggtgcc gctggcaact tctctgtgga ctctcagatt ctttactatg 1100 caatgttgggggtgaatccc cgctttgact cagcttcctc cagctactat 1150 ttggacatgc acagcctcccccatgtcatc aacccagtgg agtcccggct 1200 gggatccagt gctgcctcct tgtaccctgtgctcaacttt ctactctacg 1250 tgcctgagct tgcacactca ccgctgtaca ttcaggacaaggatggcgct 1300 ccagtggcca ccaatgcctt ccatagtccc cgctggggtg gcattatggt1350 atataatgtt gactccaaaa cctataatgc ctcagtgctg ccagtgagag 1400tcgaggtgga catggtgcga gtgatggagg tgttcctggc acagttgcgg 1450 ttgctctttgggattgctca gccccagctg cctccaaaat gcctgctttc 1500 agggcctacg agtgaagggctaatgacctg ggagctagac cggctgctct 1550 gggctcggtc agtggagaac ctggccacagccaccaccac ccttacctcc 1600 ctggcgcagc ttctgggcaa gatcagcaac attgtcattaaggacgacgt 1650 ggcatctgag gtgtacaagg ctgtagctgc cgtccagaag tcggcagaag1700 agttggcgtc tgggcacctg gcatctgcct ttgtcgccag ccaggaagct 1750gtgacatcct ctgagcttgc cttctttgac ccgtcactcc tccacctcct 1800 ttatttccctgatgaccaga agtttgccat ctacatccca ctcttcctgc 1850 ctatggctgt gcccatcctcctgtccctgg tcaagatctt cctggagacc 1900 cgcaagtcct ggagaaagcc tgagaagacagactgagcag ggcagcacct 1950 ccataggaag ccttcctttc tggccaaggt gggcggtgttagattgtgag 2000 gcacgtacat ggggcctgcc ggaatgactt aaatatttgt ctccagtctc2050 cactgttggc tctccagcaa ccaaagtaca acactccaag atgggttcat 2100cttttcttcc tttcccattc acctggctca atcctcctcc accaccaggg 2150 gcctcaaaaggcacatcatc cgggtctcct tatcttgttt gataaggctg 2200 ctgcctgtct ccctctgtggcaaggactgt ttgttctttt gccccatttc 2250 tcaacatagc acacttgtgc actgagaggagggagcatta tgggaaagtc 2300 cctgccttcc acacctctct ctagtccctg tgggacagccctagcccctg 2350 ctgtcatgaa ggggccaggc attggtcacc tgtgggacct tctccctcac2400 tcccctccct cctagttggc tttgtctgtc aggtgcagtc tggcgggagt 2450ccaggaggca gcagctcagg acatggtgct gtgtgtgtgt gtgtgtgtgt 2500 gtgtgtgtgtgtgtgtgtca gaggttccag aaagttccag atttggaatc 2550 aaacagtcct gaattcaaatccttgttttt gcacttattg tctggagagc 2600 tttggataag gtattgaatc tctctgagcctcagtttttc atttgttcaa 2650 atggcactga tgatgtctcc cttacaagat ggttgtgaggagtaaatgtg 2700 atcagcatgt aaagtgtctg gcgtgtagta ggctcttaat aaacactggc2750 tgaatatgaa ttggaatgat 2770 40 547 PRT Homo Sapien 40 Met Pro SerGlu Val Ala Arg Gly Lys Arg Ala Ala Leu Phe Phe 1 5 10 15 Ala Ala ValAla Ile Val Leu Gly Leu Pro Leu Trp Trp Lys Thr 20 25 30 Thr Glu Thr TyrArg Ala Ser Leu Pro Tyr Ser Gln Ile Ser Gly 35 40 45 Leu Asn Ala Leu GlnLeu Arg Leu Met Val Pro Val Thr Val Val 50 55 60 Phe Thr Arg Glu Ser ValPro Leu Asp Asp Gln Glu Lys Leu Pro 65 70 75 Phe Thr Val Val His Glu ArgGlu Ile Pro Leu Lys Tyr Lys Met 80 85 90 Lys Ile Lys Cys Arg Phe Gln LysAla Tyr Arg Arg Ala Leu Asp 95 100 105 His Glu Glu Glu Ala Leu Ser SerGly Ser Val Gln Glu Ala Glu 110 115 120 Ala Met Leu Asp Glu Pro Gln GluGln Ala Glu Gly Ser Leu Thr 125 130 135 Val Tyr Val Ile Ser Glu His SerSer Leu Leu Pro Gln Asp Met 140 145 150 Met Ser Tyr Ile Gly Pro Lys ArgThr Ala Val Val Arg Gly Ile 155 160 165 Met His Arg Glu Ala Phe Asn IleIle Gly Arg Arg Ile Val Gln 170 175 180 Val Ala Gln Ala Met Ser Leu ThrGlu Asp Val Leu Ala Ala Ala 185 190 195 Leu Ala Asp His Leu Pro Glu AspLys Trp Ser Ala Glu Lys Arg 200 205 210 Arg Pro Leu Lys Ser Ser Leu GlyTyr Glu Ile Thr Phe Ser Leu 215 220 225 Leu Asn Pro Asp Pro Lys Ser HisAsp Val Tyr Trp Asp Ile Glu 230 235 240 Gly Ala Val Arg Arg Tyr Val GlnPro Phe Leu Asn Ala Leu Gly 245 250 255 Ala Ala Gly Asn Phe Ser Val AspSer Gln Ile Leu Tyr Tyr Ala 260 265 270 Met Leu Gly Val Asn Pro Arg PheAsp Ser Ala Ser Ser Ser Tyr 275 280 285 Tyr Leu Asp Met His Ser Leu ProHis Val Ile Asn Pro Val Glu 290 295 300 Ser Arg Leu Gly Ser Ser Ala AlaSer Leu Tyr Pro Val Leu Asn 305 310 315 Phe Leu Leu Tyr Val Pro Glu LeuAla His Ser Pro Leu Tyr Ile 320 325 330 Gln Asp Lys Asp Gly Ala Pro ValAla Thr Asn Ala Phe His Ser 335 340 345 Pro Arg Trp Gly Gly Ile Met ValTyr Asn Val Asp Ser Lys Thr 350 355 360 Tyr Asn Ala Ser Val Leu Pro ValArg Val Glu Val Asp Met Val 365 370 375 Arg Val Met Glu Val Phe Leu AlaGln Leu Arg Leu Leu Phe Gly 380 385 390 Ile Ala Gln Pro Gln Leu Pro ProLys Cys Leu Leu Ser Gly Pro 395 400 405 Thr Ser Glu Gly Leu Met Thr TrpGlu Leu Asp Arg Leu Leu Trp 410 415 420 Ala Arg Ser Val Glu Asn Leu AlaThr Ala Thr Thr Thr Leu Thr 425 430 435 Ser Leu Ala Gln Leu Leu Gly LysIle Ser Asn Ile Val Ile Lys 440 445 450 Asp Asp Val Ala Ser Glu Val TyrLys Ala Val Ala Ala Val Gln 455 460 465 Lys Ser Ala Glu Glu Leu Ala SerGly His Leu Ala Ser Ala Phe 470 475 480 Val Ala Ser Gln Glu Ala Val ThrSer Ser Glu Leu Ala Phe Phe 485 490 495 Asp Pro Ser Leu Leu His Leu LeuTyr Phe Pro Asp Asp Gln Lys 500 505 510 Phe Ala Ile Tyr Ile Pro Leu PheLeu Pro Met Ala Val Pro Ile 515 520 525 Leu Leu Ser Leu Val Lys Ile PheLeu Glu Thr Arg Lys Ser Trp 530 535 540 Arg Lys Pro Glu Lys Thr Asp 54541 1964 DNA Homo Sapien 41 ccagctgcag agaggaggag gtgagctgca gagaagaggaggttggtgtg 50 gagcacaggc agcaccgagc ctgccccgtg agctgagggc ctgcagtctg 100cggctggaat caggatagac accaaggcag gacccccaga gatgctgaag 150 cctctttggaaagcagcagt ggcccccaca tggccatgct ccatgccgcc 200 ccgccgcccg tgggacagagaggctggcac gttgcaggtc ctgggagcgc 250 tggctgtgct gtggctgggc tccgtggctcttatctgcct cctgtggcaa 300 gtgccccgtc ctcccacctg gggccaggtg cagcccaaggacgtgcccag 350 gtcctgggag catggctcca gcccagcttg ggagcccctg gaagcagagg400 ccaggcagca gagggactcc tgccagcttg tccttgtgga aagcatcccc 450caggacctgc catctgcagc cggcagcccc tctgcccagc ctctgggcca 500 ggcctggctgcagctgctgg acactgccca ggagagcgtc cacgtggctt 550 catactactg gtccctcacagggcctgaca tcggggtcaa cgactcgtct 600 tcccagctgg gagaggctct tctgcagaagctgcagcagc tgctgggcag 650 gaacatttcc ctggctgtgg ccaccagcag cccgacactggccaggacat 700 ccaccgacct gcaggttctg gctgcccgag gtgcccatgt acgacaggtg750 cccatggggc ggctcaccag gggtgttttg cactccaaat tctgggttgt 800ggatggacgg cacatataca tgggcagtgc caacatggac tggcggtctc 850 tgacgcaggtgaaggagctt ggcgctgtca tctataactg cagccacctg 900 gcccaagacc tggagaagaccttccagacc tactgggtac tgggggtgcc 950 caaggctgtc ctccccaaaa cctggcctcagaacttctca tctcacttca 1000 accgtttcca gcccttccac ggcctctttg atggggtgcccaccactgcc 1050 tacttctcag cgtcgccacc agcactctgt ccccagggcc gcacccggga1100 cctggaggcg ctgctggcgg tgatggggag cgcccaggag ttcatctatg 1150cctccgtgat ggagtatttc cccaccacgc gcttcagcca ccccccgagg 1200 tactggccggtgctggacaa cgcgctgcgg gcggcagcct tcggcaaggg 1250 cgtgcgcgtg cgcctgctggtcggctgcgg actcaacacg gaccccacca 1300 tgttccccta cctgcggtcc ctgcaggcgctcagcaaccc cgcggccaac 1350 gtctctgtgg acgtgaaagt cttcatcgtg ccggtggggaaccattccaa 1400 catcccattc agcagggtga accacagcaa gttcatggtc acggagaagg1450 cagcctacat aggcacctcc aactggtcgg aggattactt cagcagcacg 1500gcgggggtgg gcttggtggt cacccagagc cctggcgcgc agcccgcggg 1550 ggccacggtgcaggagcagc tgcggcagct ctttgagcgg gactggagtt 1600 cgcgctacgc cgtcggcctggacggacagg ctccgggcca ggactgcgtt 1650 tggcagggct gaggggggcc tctttttctctcggcgaccc cgccccgcac 1700 gcgccctccc ctctgacccc ggcctgggct tcagccgcttcctcccgcaa 1750 gcagcccggg tccgcactgc gccaggagcc gcctgcgacc gcccgggcgt1800 cgcaaaccgc ccgcctgctc tctgatttcc gagtccagcc ccccctgagc 1850cccacctcct ccagggagcc ctccaggaag ccccttccct gactcctggc 1900 ccacaggccaggcctaaaaa aaactcgtgg cttcaaaaaa aaaaaaaaaa 1950 aaaaaaaaaa aaaa 1964 42489 PRT Homo Sapien 42 Met Pro Pro Arg Arg Pro Trp Asp Arg Glu Ala GlyThr Leu Gln 1 5 10 15 Val Leu Gly Ala Leu Ala Val Leu Trp Leu Gly SerVal Ala Leu 20 25 30 Ile Cys Leu Leu Trp Gln Val Pro Arg Pro Pro Thr TrpGly Gln 35 40 45 Val Gln Pro Lys Asp Val Pro Arg Ser Trp Glu His Gly SerSer 50 55 60 Pro Ala Trp Glu Pro Leu Glu Ala Glu Ala Arg Gln Gln Arg Asp65 70 75 Ser Cys Gln Leu Val Leu Val Glu Ser Ile Pro Gln Asp Leu Pro 8085 90 Ser Ala Ala Gly Ser Pro Ser Ala Gln Pro Leu Gly Gln Ala Trp 95 100105 Leu Gln Leu Leu Asp Thr Ala Gln Glu Ser Val His Val Ala Ser 110 115120 Tyr Tyr Trp Ser Leu Thr Gly Pro Asp Ile Gly Val Asn Asp Ser 125 130135 Ser Ser Gln Leu Gly Glu Ala Leu Leu Gln Lys Leu Gln Gln Leu 140 145150 Leu Gly Arg Asn Ile Ser Leu Ala Val Ala Thr Ser Ser Pro Thr 155 160165 Leu Ala Arg Thr Ser Thr Asp Leu Gln Val Leu Ala Ala Arg Gly 170 175180 Ala His Val Arg Gln Val Pro Met Gly Arg Leu Thr Arg Gly Val 185 190195 Leu His Ser Lys Phe Trp Val Val Asp Gly Arg His Ile Tyr Met 200 205210 Gly Ser Ala Asn Met Asp Trp Arg Ser Leu Thr Gln Val Lys Glu 215 220225 Leu Gly Ala Val Ile Tyr Asn Cys Ser His Leu Ala Gln Asp Leu 230 235240 Glu Lys Thr Phe Gln Thr Tyr Trp Val Leu Gly Val Pro Lys Ala 245 250255 Val Leu Pro Lys Thr Trp Pro Gln Asn Phe Ser Ser His Phe Asn 260 265270 Arg Phe Gln Pro Phe His Gly Leu Phe Asp Gly Val Pro Thr Thr 275 280285 Ala Tyr Phe Ser Ala Ser Pro Pro Ala Leu Cys Pro Gln Gly Arg 290 295300 Thr Arg Asp Leu Glu Ala Leu Leu Ala Val Met Gly Ser Ala Gln 305 310315 Glu Phe Ile Tyr Ala Ser Val Met Glu Tyr Phe Pro Thr Thr Arg 320 325330 Phe Ser His Pro Pro Arg Tyr Trp Pro Val Leu Asp Asn Ala Leu 335 340345 Arg Ala Ala Ala Phe Gly Lys Gly Val Arg Val Arg Leu Leu Val 350 355360 Gly Cys Gly Leu Asn Thr Asp Pro Thr Met Phe Pro Tyr Leu Arg 365 370375 Ser Leu Gln Ala Leu Ser Asn Pro Ala Ala Asn Val Ser Val Asp 380 385390 Val Lys Val Phe Ile Val Pro Val Gly Asn His Ser Asn Ile Pro 395 400405 Phe Ser Arg Val Asn His Ser Lys Phe Met Val Thr Glu Lys Ala 410 415420 Ala Tyr Ile Gly Thr Ser Asn Trp Ser Glu Asp Tyr Phe Ser Ser 425 430435 Thr Ala Gly Val Gly Leu Val Val Thr Gln Ser Pro Gly Ala Gln 440 445450 Pro Ala Gly Ala Thr Val Gln Glu Gln Leu Arg Gln Leu Phe Glu 455 460465 Arg Asp Trp Ser Ser Arg Tyr Ala Val Gly Leu Asp Gly Gln Ala 470 475480 Pro Gly Gln Asp Cys Val Trp Gln Gly 485 43 1130 DNA Homo Sapien 43gggcctggcg atccggatcc cgcaggcgcg ctggctgcgc tgcccggctg 50 tctgtcgtcatggtggggcc ctgggtgtat ctggtggcgg cagttttgct 100 catcggcctg atcctcttcctgactcgcag ccggggtcgg gcggcagcag 150 ctgacggaga accactgcac aatgaggaagagagggcagg agcaggccag 200 gtaggccgct ctttgcccca ggagtctgaa gaacagagaactggaagcag 250 accccggcgt cggagggact tgggcagccg tctacaggcc cagcgtcgag300 cccagcgagt ggcctgggaa gacggggatg agaatgtggg tcaaactgtt 350attccagccc aggaggaaga aggcattgag aagccagcag aagttcaccc 400 aacagggaaaattggagcca agaaactacg gaagctagag gaaaaacagg 450 ctcgaaaggc tcagcgagaggcagaggagg ctgaacgtga agaacggaaa 500 cgcctagagt cccaacgtga ggccgaatggaagaaggaag aggaacggct 550 tcgcctgaag gaagaacaga aggaggagga agagaggaaggctcaggagg 600 agcaggcccg gcgggatcac gaggagtacc tgaaactgaa ggaggccttc650 gtggtagaag aagaaggtgt tagcgaaacc atgactgagg agcagtctca 700cagcttcctg acagaattca tcaattacat caagaagtcc aaggttgtgc 750 ttttggaagatctggctttc cagatgggcc taaggactca ggacgccata 800 aaccgcatcc aggacctgctgacggagggg actctaacag gtgtgattga 850 cgaccggggc aagtttatct acataaccccagaggaactg gctgccgtgg 900 ccaatttcat ccgacagcgg ggccgggtgt ccatcacagagcttgcccag 950 gccagcaact ccctcatctc ctggggccag gacctccctg cccaggcttc1000 agcctgactc cagtccttcc ttgagtgtat cctgtggcct acatgtgtct 1050tcatccttcc ctaatgccgt cttggggcag ggatggaata tgaccagaaa 1100 gttgtggattaaaggcctgt gaatactgaa 1130 44 315 PRT Homo Sapien 44 Met Val Gly Pro TrpVal Tyr Leu Val Ala Ala Val Leu Leu Ile 1 5 10 15 Gly Leu Ile Leu PheLeu Thr Arg Ser Arg Gly Arg Ala Ala Ala 20 25 30 Ala Asp Gly Glu Pro LeuHis Asn Glu Glu Glu Arg Ala Gly Ala 35 40 45 Gly Gln Val Gly Arg Ser LeuPro Gln Glu Ser Glu Glu Gln Arg 50 55 60 Thr Gly Ser Arg Pro Arg Arg ArgArg Asp Leu Gly Ser Arg Leu 65 70 75 Gln Ala Gln Arg Arg Ala Gln Arg ValAla Trp Glu Asp Gly Asp 80 85 90 Glu Asn Val Gly Gln Thr Val Ile Pro AlaGln Glu Glu Glu Gly 95 100 105 Ile Glu Lys Pro Ala Glu Val His Pro ThrGly Lys Ile Gly Ala 110 115 120 Lys Lys Leu Arg Lys Leu Glu Glu Lys GlnAla Arg Lys Ala Gln 125 130 135 Arg Glu Ala Glu Glu Ala Glu Arg Glu GluArg Lys Arg Leu Glu 140 145 150 Ser Gln Arg Glu Ala Glu Trp Lys Lys GluGlu Glu Arg Leu Arg 155 160 165 Leu Lys Glu Glu Gln Lys Glu Glu Glu GluArg Lys Ala Gln Glu 170 175 180 Glu Gln Ala Arg Arg Asp His Glu Glu TyrLeu Lys Leu Lys Glu 185 190 195 Ala Phe Val Val Glu Glu Glu Gly Val SerGlu Thr Met Thr Glu 200 205 210 Glu Gln Ser His Ser Phe Leu Thr Glu PheIle Asn Tyr Ile Lys 215 220 225 Lys Ser Lys Val Val Leu Leu Glu Asp LeuAla Phe Gln Met Gly 230 235 240 Leu Arg Thr Gln Asp Ala Ile Asn Arg IleGln Asp Leu Leu Thr 245 250 255 Glu Gly Thr Leu Thr Gly Val Ile Asp AspArg Gly Lys Phe Ile 260 265 270 Tyr Ile Thr Pro Glu Glu Leu Ala Ala ValAla Asn Phe Ile Arg 275 280 285 Gln Arg Gly Arg Val Ser Ile Thr Glu LeuAla Gln Ala Ser Asn 290 295 300 Ser Leu Ile Ser Trp Gly Gln Asp Leu ProAla Gln Ala Ser Ala 305 310 315 45 1977 DNA Homo Sapien 45 acgggccgcagcggcagtga cgtagggttg gcgcacggat ccgttgcggc 50 tgcagctctg cagtcgggccgttccttcgc cgccgccagg ggtagcggtg 100 tagctgcgca gcgtcgcgcg cgctaccgcacccaggttcg gcccgtaggc 150 gtctggcagc ccggcgccat cttcatcgag cgccatggccgcagcctgcg 200 ggccgggagc ggccgggtac tgcttgctcc tcggcttgca tttgtttctg250 ctgaccgcgg gccctgccct gggctggaac gaccctgaca gaatgttgct 300gcgggatgta aaagctctta ccctccacta tgaccgctat accacctccc 350 gcaggctggatcccatccca cagttgaaat gtgttggagg cacagctggt 400 tgtgattctt ataccccaaaagtcatacag tgtcagaaca aaggctggga 450 tgggtatgat gtacagtggg aatgtaagacggacttagat attgcataca 500 aatttggaaa aactgtggtg agctgtgaag gctatgagtcctctgaagac 550 cagtatgtac taagaggttc ttgtggcttg gagtataatt tagattatac600 agaacttggc ctgcagaaac tgaaggagtc tggaaagcag cacggctttg 650cctctttctc tgattattat tataagtggt cctcggcgga ttcctgtaac 700 atgagtggattgattaccat cgtggtactc cttgggatcg cctttgtagt 750 ctataagctg ttcctgagtgacgggcagta ttctcctcca ccgtactctg 800 agtatcctcc attttcccac cgttaccagagattcaccaa ctcagcagga 850 cctcctcccc caggctttaa gtctgagttc acaggaccacagaatactgg 900 ccatggtgca acttctggtt ttggcagtgc ttttacagga caacaaggat950 atgaaaattc aggaccaggg ttctggacag gcttgggaac tggtggaata 1000ctaggatatt tgtttggcag caatagagcg gcaacaccct tctcagactc 1050 gtggtactacccgtcctatc ctccctccta ccctggcacg tggaataggg 1100 cttactcacc ccttcatggaggctcgggca gctattcggt atgttcaaac 1150 tcagacacga aaaccagaac tgcatcaggatatggtggta ccaggagacg 1200 ataaagtaga aagttggagt caaacactgg atgcagaaattttggatttt 1250 tcatcacttt ctctttagaa aaaaagtact acctgttaac aattgggaaa1300 aggggatatt caaaagttct gtggtgttat gtccagtgta gctttttgta 1350ttctattatt tgaggctaaa agttgatgtg tgacaaaata cttatgtgtt 1400 gtatgtcagtgtaacatgca gatgtatatt gcagtttttg aaagtgatca 1450 ttactgtgga atgctaaaaatacattaatt tctaaaacct gtgatgccct 1500 aagaagcatt aagaatgaag gtgttgtactaatagaaact aagtacagaa 1550 aatttcagtt ttaggtggtt gtagctgatg agttattacctcatagagac 1600 tataatattc tatttggtat tatattattt gatgtttgct gttcttcaaa1650 catttaaatc aagctttgga ctaattatgc taatttgtga gttctgatca 1700cttttgagct ctgaagcttt gaatcattca gtggtggaga tggccttctg 1750 gtaactgaatattaccttct gtaggaaaag gtggaaaata agcatctaga 1800 aggttgttgt gaatgactctgtgctggcaa aaatgcttga aacctctata 1850 tttctttcgt tcataagagg taaaggtcaaatttttcaac aaaagtcttt 1900 taataacaaa agcatgcagt tctctgtgaa atctcaaatattgttgtaat 1950 agtctgtttc aatcttaaaa agaatca 1977 46 339 PRT HomoSapien 46 Met Ala Ala Ala Cys Gly Pro Gly Ala Ala Gly Tyr Cys Leu Leu 15 10 15 Leu Gly Leu His Leu Phe Leu Leu Thr Ala Gly Pro Ala Leu Gly 2025 30 Trp Asn Asp Pro Asp Arg Met Leu Leu Arg Asp Val Lys Ala Leu 35 4045 Thr Leu His Tyr Asp Arg Tyr Thr Thr Ser Arg Arg Leu Asp Pro 50 55 60Ile Pro Gln Leu Lys Cys Val Gly Gly Thr Ala Gly Cys Asp Ser 65 70 75 TyrThr Pro Lys Val Ile Gln Cys Gln Asn Lys Gly Trp Asp Gly 80 85 90 Tyr AspVal Gln Trp Glu Cys Lys Thr Asp Leu Asp Ile Ala Tyr 95 100 105 Lys PheGly Lys Thr Val Val Ser Cys Glu Gly Tyr Glu Ser Ser 110 115 120 Glu AspGln Tyr Val Leu Arg Gly Ser Cys Gly Leu Glu Tyr Asn 125 130 135 Leu AspTyr Thr Glu Leu Gly Leu Gln Lys Leu Lys Glu Ser Gly 140 145 150 Lys GlnHis Gly Phe Ala Ser Phe Ser Asp Tyr Tyr Tyr Lys Trp 155 160 165 Ser SerAla Asp Ser Cys Asn Met Ser Gly Leu Ile Thr Ile Val 170 175 180 Val LeuLeu Gly Ile Ala Phe Val Val Tyr Lys Leu Phe Leu Ser 185 190 195 Asp GlyGln Tyr Ser Pro Pro Pro Tyr Ser Glu Tyr Pro Pro Phe 200 205 210 Ser HisArg Tyr Gln Arg Phe Thr Asn Ser Ala Gly Pro Pro Pro 215 220 225 Pro GlyPhe Lys Ser Glu Phe Thr Gly Pro Gln Asn Thr Gly His 230 235 240 Gly AlaThr Ser Gly Phe Gly Ser Ala Phe Thr Gly Gln Gln Gly 245 250 255 Tyr GluAsn Ser Gly Pro Gly Phe Trp Thr Gly Leu Gly Thr Gly 260 265 270 Gly IleLeu Gly Tyr Leu Phe Gly Ser Asn Arg Ala Ala Thr Pro 275 280 285 Phe SerAsp Ser Trp Tyr Tyr Pro Ser Tyr Pro Pro Ser Tyr Pro 290 295 300 Gly ThrTrp Asn Arg Ala Tyr Ser Pro Leu His Gly Gly Ser Gly 305 310 315 Ser TyrSer Val Cys Ser Asn Ser Asp Thr Lys Thr Arg Thr Ala 320 325 330 Ser GlyTyr Gly Gly Thr Arg Arg Arg 335 47 1766 DNA Homo Sapien 47 cccggagccggggagggagg gagcgaggtt cggacaccgg cggcggctgc 50 ctggcctttc catgagcccgcggcggaccc tcccgcgccc cctctcgctc 100 tgcctctccc tctgcctctg cctctgcctggccgcggctc tgggaagtgc 150 gcagtccggg tcgtgtaggg ataaaaagaa ctgtaaggtggtcttttccc 200 agcaggaact gaggaagcgg ctaacacccc tgcagtacca tgtcactcag250 gagaaaggga ccgaaagtgc ctttgaagga gaatacacac atcacaaaga 300tcctggaata tataaatgtg ttgtttgtgg aactccattg tttaagtcag 350 aaaccaaatttgactccggt tcaggttggc cttcattcca cgatgtgatc 400 aattctgagg caatcacattcacagatgac ttttcctatg ggatgcacag 450 ggtggaaaca agctgctctc agtgtggtgctcaccttggg cacatttttg 500 atgatgggcc tcgtccaact gggaaaagat actgcataaattcggctgcc 550 ttgtctttta cacctgcgga tagcagtggc accgccgagg gaggcagtgg600 ggtcgccagc ccggcccagg cagacaaagc ggagctctag agtaatggag 650agtgatggaa acaaagtgta cttaatgcac agcttattaa aaaaatcaaa 700 attgttatcttaatagatat attttttcaa aaactataag ggcagttttg 750 tgctattgat attttttcttcttttgctta aacagaagcc ctggccatcc 800 atgtattttg caattgacta gatcaagaactgtttatagc tttagcaaat 850 ggagacagct ttgtgaaact tcttcacaag ccacttataccctttggcat 900 tcttttcttt gagcacatgg cttcttttgc agtttttccc cctttgattc950 agaagcagag ggttcatggt cttcaaacat gaaaatagag atctcctctg 1000cagtgtagag accagagctg ggcagtgcag ggcatggaga cctgcaagac 1050 acatggccttgaggcctttg cacagaccca cctaagataa ggttggagtg 1100 atgttttaat gagactgttcagctttgtgg aaagtttgag ctaaggtcat 1150 tttttttttt ctcactgaaa gggtgtgaaggtctaaagtc tttccttatg 1200 ttaaattgtt gccagatcca aaggggcata ctgagtgttgtggcagagaa 1250 gtaaacatta ccacactgtt aggcctttat tttattttat tttccatcga1300 aagcattgga ggcccagtgc aatggctcac gcctgtgatc ccagcacttt 1350gggaggccaa ggcgggtgga tcacgaggtc aggagatgga gaccatcctg 1400 gctaacatggtgaaaccccg tctctactaa aaatacgaaa aattagccag 1450 gcgtggtggt gggcacctgtagtcccagct actcaggagg ctgaggcagg 1500 agaatggcgt gaacccggaa ggcggagcttgcagttagcc gagatcatgc 1550 cactgcactc cagcctacat gacaatgtga cactccatctcaaaaaataa 1600 taataataac aatataagaa ctagctgggc atggtggcgc atgcatgtag1650 tcccagctac tcctgaggct cagtcaggag aatcgcttga acttgggagg 1700cggaggttgc agtgagctga gctcatacca ctgcactcca gcctgaacag 1750 agtgagatcctgtcaa 1766 48 192 PRT Homo Sapien 48 Met Ser Pro Arg Arg Thr Leu ProArg Pro Leu Ser Leu Cys Leu 1 5 10 15 Ser Leu Cys Leu Cys Leu Cys LeuAla Ala Ala Leu Gly Ser Ala 20 25 30 Gln Ser Gly Ser Cys Arg Asp Lys LysAsn Cys Lys Val Val Phe 35 40 45 Ser Gln Gln Glu Leu Arg Lys Arg Leu ThrPro Leu Gln Tyr His 50 55 60 Val Thr Gln Glu Lys Gly Thr Glu Ser Ala PheGlu Gly Glu Tyr 65 70 75 Thr His His Lys Asp Pro Gly Ile Tyr Lys Cys ValVal Cys Gly 80 85 90 Thr Pro Leu Phe Lys Ser Glu Thr Lys Phe Asp Ser GlySer Gly 95 100 105 Trp Pro Ser Phe His Asp Val Ile Asn Ser Glu Ala IleThr Phe 110 115 120 Thr Asp Asp Phe Ser Tyr Gly Met His Arg Val Glu ThrSer Cys 125 130 135 Ser Gln Cys Gly Ala His Leu Gly His Ile Phe Asp AspGly Pro 140 145 150 Arg Pro Thr Gly Lys Arg Tyr Cys Ile Asn Ser Ala AlaLeu Ser 155 160 165 Phe Thr Pro Ala Asp Ser Ser Gly Thr Ala Glu Gly GlySer Gly 170 175 180 Val Ala Ser Pro Ala Gln Ala Asp Lys Ala Glu Leu 185190 49 2065 DNA Homo Sapien 49 cccaaagagg tgaggagccg gcagcgggggcggctgtaac tgtgaggaag 50 gctgcagagt ggcgacgtct acgccgtagg ttggaggctgtggggggtgg 100 ccgggcgcca gctcccaggc cgcagaagtg acctgcggtg gagttccctc150 ctcgctgctg gagaacggag ggagaaggtt gctggccggg tgaaagtgcc 200tccctctgct tgacggggct gaggggcccg aagtctaggg cgtccgtagt 250 cgccccggcctccgtgaagc cccaggtcta gagatatgac ccgagagtgc 300 ccatctccgg ccccggggcctggggctccg ctgagtggat cggtgctggc 350 agaggcggca gtagtgtttg cagtggtgctgagcatccac gcaaccgtat 400 gggaccgata ctcgtggtgc gccgtggccc tcgcagtgcaggccttctac 450 gtccaataca agtgggaccg gctgctacag cagggaagcg ccgtcttcca500 gttccgaatg tccgcaaaca gtggcctatt gcccgcctcc atggtcatgc 550ctttgcttgg actagtcatg aaggagcggt gccagactgc tgggaacccg 600 ttctttgagcgttttggcat tgtggtggca gccactggca tggcagtggc 650 cctcttctca tcagtgttggcgctcggcat cactcgccca gtgccaacca 700 acacttgtgt catcttgggc ttggctggaggtgttatcat ttatatcatg 750 aagcactcgt tgagcgtggg ggaggtgatc gaagtcctggaagtccttct 800 gatcttcgtt tatctcaaca tgatcctgct gtacctgctg ccccgctgct850 tcacccctgg tgaggcactg ctggtattgg gtggcattag ctttgtcctc 900aaccagctca tcaagcgctc tctgacactg gtggaaagtc agggggaccc 950 agtggacttcttcctgctgg tggtggtagt agggatggta ctcatgggca 1000 ttttcttcag cactctgtttgtcttcatgg actcaggcac ctgggcctcc 1050 tccatcttct tccacctcat gacctgtgtgctgagccttg gtgtggtcct 1100 accctggctg caccggctca tccgcaggaa tcccctgctctggcttcttc 1150 agtttctctt ccagacagac acccgcatct acctcctagc ctattggtct1200 ctgctggcca ccttggcctg cctggtggtg ctgtaccaga atgccaagcg 1250gtcatcttcc gagtccaaga agcaccaggc ccccaccatc gcccgaaagt 1300 atttccacctcattgtggta gccacctaca tcccaggtat catctttgac 1350 cggccactgc tctatgtagccgccactgta tgcctggcgg tcttcatctt 1400 cctggagtat gtgcgctact tccgcatcaagcctttgggt cacactctac 1450 ggagcttcct gtcccttttt ctggatgaac gagacagtggaccactcatt 1500 ctgacacaca tctacctgct cctgggcatg tctcttccca tctggctgat1550 ccccagaccc tgcacacaga agggtagcct gggaggagcc agggccctcg 1600tcccctatgc cggtgtcctg gctgtgggtg tgggtgatac tgtggcctcc 1650 atcttcggtagcaccatggg ggagatccgc tggcctggaa ccaaaaagac 1700 ttttgagggg accatgacatctatatttgc gcagatcatt tctgtagctc 1750 tgatcttaat ctttgacagt ggagtggacctaaactacag ttatgcttgg 1800 attttggggt ccatcagcac tgtgtccctc ctggaagcatacactacaca 1850 gatagacaat ctccttctgc ctctctacct cctgatattg ctgatggcct1900 agctgttaca gtgcagcagc agtgacggag gaaacagaca tggggagggt 1950gaacagtccc cacagcagac agctacttgg gcatgaagag ccaaggtgtg 2000 aaaagcagatttgatttttc agttgattca gatttaaaat aaaaagcaaa 2050 gctctcctag ttcta 206550 538 PRT Homo Sapien 50 Met Thr Arg Glu Cys Pro Ser Pro Ala Pro GlyPro Gly Ala Pro 1 5 10 15 Leu Ser Gly Ser Val Leu Ala Glu Ala Ala ValVal Phe Ala Val 20 25 30 Val Leu Ser Ile His Ala Thr Val Trp Asp Arg TyrSer Trp Cys 35 40 45 Ala Val Ala Leu Ala Val Gln Ala Phe Tyr Val Gln TyrLys Trp 50 55 60 Asp Arg Leu Leu Gln Gln Gly Ser Ala Val Phe Gln Phe ArgMet 65 70 75 Ser Ala Asn Ser Gly Leu Leu Pro Ala Ser Met Val Met Pro Leu80 85 90 Leu Gly Leu Val Met Lys Glu Arg Cys Gln Thr Ala Gly Asn Pro 95100 105 Phe Phe Glu Arg Phe Gly Ile Val Val Ala Ala Thr Gly Met Ala 110115 120 Val Ala Leu Phe Ser Ser Val Leu Ala Leu Gly Ile Thr Arg Pro 125130 135 Val Pro Thr Asn Thr Cys Val Ile Leu Gly Leu Ala Gly Gly Val 140145 150 Ile Ile Tyr Ile Met Lys His Ser Leu Ser Val Gly Glu Val Ile 155160 165 Glu Val Leu Glu Val Leu Leu Ile Phe Val Tyr Leu Asn Met Ile 170175 180 Leu Leu Tyr Leu Leu Pro Arg Cys Phe Thr Pro Gly Glu Ala Leu 185190 195 Leu Val Leu Gly Gly Ile Ser Phe Val Leu Asn Gln Leu Ile Lys 200205 210 Arg Ser Leu Thr Leu Val Glu Ser Gln Gly Asp Pro Val Asp Phe 215220 225 Phe Leu Leu Val Val Val Val Gly Met Val Leu Met Gly Ile Phe 230235 240 Phe Ser Thr Leu Phe Val Phe Met Asp Ser Gly Thr Trp Ala Ser 245250 255 Ser Ile Phe Phe His Leu Met Thr Cys Val Leu Ser Leu Gly Val 260265 270 Val Leu Pro Trp Leu His Arg Leu Ile Arg Arg Asn Pro Leu Leu 275280 285 Trp Leu Leu Gln Phe Leu Phe Gln Thr Asp Thr Arg Ile Tyr Leu 290295 300 Leu Ala Tyr Trp Ser Leu Leu Ala Thr Leu Ala Cys Leu Val Val 305310 315 Leu Tyr Gln Asn Ala Lys Arg Ser Ser Ser Glu Ser Lys Lys His 320325 330 Gln Ala Pro Thr Ile Ala Arg Lys Tyr Phe His Leu Ile Val Val 335340 345 Ala Thr Tyr Ile Pro Gly Ile Ile Phe Asp Arg Pro Leu Leu Tyr 350355 360 Val Ala Ala Thr Val Cys Leu Ala Val Phe Ile Phe Leu Glu Tyr 365370 375 Val Arg Tyr Phe Arg Ile Lys Pro Leu Gly His Thr Leu Arg Ser 380385 390 Phe Leu Ser Leu Phe Leu Asp Glu Arg Asp Ser Gly Pro Leu Ile 395400 405 Leu Thr His Ile Tyr Leu Leu Leu Gly Met Ser Leu Pro Ile Trp 410415 420 Leu Ile Pro Arg Pro Cys Thr Gln Lys Gly Ser Leu Gly Gly Ala 425430 435 Arg Ala Leu Val Pro Tyr Ala Gly Val Leu Ala Val Gly Val Gly 440445 450 Asp Thr Val Ala Ser Ile Phe Gly Ser Thr Met Gly Glu Ile Arg 455460 465 Trp Pro Gly Thr Lys Lys Thr Phe Glu Gly Thr Met Thr Ser Ile 470475 480 Phe Ala Gln Ile Ile Ser Val Ala Leu Ile Leu Ile Phe Asp Ser 485490 495 Gly Val Asp Leu Asn Tyr Ser Tyr Ala Trp Ile Leu Gly Ser Ile 500505 510 Ser Thr Val Ser Leu Leu Glu Ala Tyr Thr Thr Gln Ile Asp Asn 515520 525 Leu Leu Leu Pro Leu Tyr Leu Leu Ile Leu Leu Met Ala 530 535 513476 DNA Homo Sapien 51 gctctatgcc gcctaccttg ctctcgccgc tgctgccggagccgaagcag 50 agaaggcagc gggtcccgtg accgtcccga gagccccgcg ctcccgacca 100gggggcgggg gcggccccgg ggagggcggg gcaggggcgg ggggaagaaa 150 gggggttttgtgctgcgccg ggagggccgg cgccctcttc cgaatgtcct 200 gcggccccag cctctcctcacgctcgcgca gtctccgccg cagtctcagc 250 tgcagctgca ggactgagcc gtgcacccggaggagacccc cggaggaggc 300 gacaaacttc gcagtgccgc gacccaaccc cagccctgggtagcctgcag 350 catggcccag ctgttcctgc ccctgctggc agccctggtc ctggcccagg400 ctcctgcagc tttagcagat gttctggaag gagacagctc agaggaccgc 450gcttttcgcg tgcgcatcgc gggcgacgcg ccactgcagg gcgtgctcgg 500 cggcgccctcaccatccctt gccacgtcca ctacctgcgg ccaccgccga 550 gccgccgggc tgtgctgggctctccgcggg tcaagtggac tttcctgtcc 600 cggggccggg aggcagaggt gctggtggcgcggggagtgc gcgtcaaggt 650 gaacgaggcc taccggttcc gcgtggcact gcctgcgtacccagcgtcgc 700 tcaccgacgt ctccctggcg ctgagcgagc tgcgccccaa cgactcaggt750 atctatcgct gtgaggtcca gcacggcatc gatgacagca gcgacgctgt 800ggaggtcaag gtcaaagggg tcgtctttct ctaccgagag ggctctgccc 850 gctatgctttctccttttct ggggcccagg aggcctgtgc ccgcattgga 900 gcccacatcg ccaccccggagcagctctat gccgcctacc ttgggggcta 950 tgagcaatgt gatgctggct ggctgtcggatcagaccgtg aggtatccca 1000 tccagacccc acgagaggcc tgttacggag acatggatggcttccccggg 1050 gtccggaact atggtgtggt ggacccggat gacctctatg atgtgtactg1100 ttatgctgaa gacctaaatg gagaactgtt cctgggtgac cctccagaga 1150agctgacatt ggaggaagca cgggcgtact gccaggagcg gggtgcagag 1200 attgccaccacgggccaact gtatgcagcc tgggatggtg gcctggacca 1250 ctgcagccca gggtggctagctgatggcag tgtgcgctac cccatcgtca 1300 cacccagcca gcgctgtggt gggggcttgcctggtgtcaa gactctcttc 1350 ctcttcccca accagactgg cttccccaat aagcacagccgcttcaacgt 1400 ctactgcttc cgagactcgg cccagccttc tgccatccct gaggcctcca1450 acccagcctc caacccagcc tctgatggac tagaggctat cgtcacagtg 1500acagagaccc tggaggaact gcagctgcct caggaagcca cagagagtga 1550 atcccgtggggccatctact ccatccccat catggaggac ggaggaggtg 1600 gaagctccac tccagaagacccagcagagg cccctaggac gctcctagaa 1650 tttgaaacac aatccatggt accgcccacggggttctcag aagaggaagg 1700 taaggcattg gaggaagaag agaaatatga agatgaagaagagaaagagg 1750 aggaagaaga agaggaggag gtggaggatg aggctctgtg ggcatggccc1800 agcgagctca gcagcccggg ccctgaggcc tctctcccca ctgagccagc 1850agcccaggag aagtcactct cccaggcgcc agcaagggca gtcctgcagc 1900 ctggtgcatcaccacttcct gatggagagt cagaagcttc caggcctcca 1950 agggtccatg gaccacctactgagactctg cccactccca gggagaggaa 2000 cctagcatcc ccatcacctt ccactctggttgaggcaaga gaggtggggg 2050 aggcaactgg tggtcctgag ctatctgggg tccctcgaggagagagcgag 2100 gagacaggaa gctccgaggg tgccccttcc ctgcttccag ccacacgggc2150 ccctgagggt accagggagc tggaggcccc ctctgaagat aattctggaa 2200gaactgcccc agcagggacc tcagtgcagg cccagccagt gctgcccact 2250 gacagcgccagccgaggtgg agtggccgtg gtccccgcat caggtgactg 2300 tgtccccagc ccctgccacaatggtgggac atgcttggag gaggaggaag 2350 gggtccgctg cctatgtctg cctggctatgggggggacct gtgcgatgtt 2400 ggcctccgct tctgcaaccc cggctgggac gccttccagggcgcctgcta 2450 caagcacttt tccacacgaa ggagctggga ggaggcagag acccagtgcc2500 ggatgtacgg cgcgcatctg gccagcatca gcacacccga ggaacaggac 2550ttcatcaaca accggtaccg ggagtaccag tggatcggac tcaacgacag 2600 gaccatcgaaggcgacttct tgtggtcgga tggcgtcccc ctgctctatg 2650 agaactggaa ccctgggcagcctgacagct acttcctgtc tggagagaac 2700 tgcgtggtca tggtgtggca tgatcagggacaatggagtg acgtgccctg 2750 caactaccac ctgtcctaca cctgcaagat ggggctggtgtcctgtgggc 2800 cgccaccgga gctgcccctg gctcaagtgt tcggccgccc acggctgcgc2850 tatgaggtgg acactgtgct tcgctaccgg tgccgggaag gactggccca 2900gcgcaatctg ccgctgatcc gatgccaaga gaacggtcgt tgggaggccc 2950 cccagatctcctgtgtgccc agaagacctg cccgagctct gcacccagag 3000 gaggacccag aaggacgtcaggggaggcta ctgggacgct ggaaggcgct 3050 gttgatcccc ccttccagcc ccatgccaggtccctagggg gcaaggcctt 3100 gaacactgcc ggccacagca ctgccctgtc acccaaattttccctcacac 3150 cttgcgctcc cgccaccaca ggaagtgaca acatgacgag gggtggtgct3200 ggagtccagg tgacagttcc tgaaggggct tctgggaaat acctaggagg 3250ctccagccca gcccaggccc tctcccccta ccctgggcac cagatcttcc 3300 atcagggccggagtaaatcc ctaagtgcct caactgccct ctccctggca 3350 gccatcttgt cccctctattcctctaggga gcactgtgcc cactctttct 3400 gggttttcca agggaatggg cttgcaggatggagtgtctg taaaatcaac 3450 aggaaataaa actgtgtatg agccca 3476 52 911 PRTHomo Sapien 52 Met Ala Gln Leu Phe Leu Pro Leu Leu Ala Ala Leu Val LeuAla 1 5 10 15 Gln Ala Pro Ala Ala Leu Ala Asp Val Leu Glu Gly Asp SerSer 20 25 30 Glu Asp Arg Ala Phe Arg Val Arg Ile Ala Gly Asp Ala Pro Leu35 40 45 Gln Gly Val Leu Gly Gly Ala Leu Thr Ile Pro Cys His Val His 5055 60 Tyr Leu Arg Pro Pro Pro Ser Arg Arg Ala Val Leu Gly Ser Pro 65 7075 Arg Val Lys Trp Thr Phe Leu Ser Arg Gly Arg Glu Ala Glu Val 80 85 90Leu Val Ala Arg Gly Val Arg Val Lys Val Asn Glu Ala Tyr Arg 95 100 105Phe Arg Val Ala Leu Pro Ala Tyr Pro Ala Ser Leu Thr Asp Val 110 115 120Ser Leu Ala Leu Ser Glu Leu Arg Pro Asn Asp Ser Gly Ile Tyr 125 130 135Arg Cys Glu Val Gln His Gly Ile Asp Asp Ser Ser Asp Ala Val 140 145 150Glu Val Lys Val Lys Gly Val Val Phe Leu Tyr Arg Glu Gly Ser 155 160 165Ala Arg Tyr Ala Phe Ser Phe Ser Gly Ala Gln Glu Ala Cys Ala 170 175 180Arg Ile Gly Ala His Ile Ala Thr Pro Glu Gln Leu Tyr Ala Ala 185 190 195Tyr Leu Gly Gly Tyr Glu Gln Cys Asp Ala Gly Trp Leu Ser Asp 200 205 210Gln Thr Val Arg Tyr Pro Ile Gln Thr Pro Arg Glu Ala Cys Tyr 215 220 225Gly Asp Met Asp Gly Phe Pro Gly Val Arg Asn Tyr Gly Val Val 230 235 240Asp Pro Asp Asp Leu Tyr Asp Val Tyr Cys Tyr Ala Glu Asp Leu 245 250 255Asn Gly Glu Leu Phe Leu Gly Asp Pro Pro Glu Lys Leu Thr Leu 260 265 270Glu Glu Ala Arg Ala Tyr Cys Gln Glu Arg Gly Ala Glu Ile Ala 275 280 285Thr Thr Gly Gln Leu Tyr Ala Ala Trp Asp Gly Gly Leu Asp His 290 295 300Cys Ser Pro Gly Trp Leu Ala Asp Gly Ser Val Arg Tyr Pro Ile 305 310 315Val Thr Pro Ser Gln Arg Cys Gly Gly Gly Leu Pro Gly Val Lys 320 325 330Thr Leu Phe Leu Phe Pro Asn Gln Thr Gly Phe Pro Asn Lys His 335 340 345Ser Arg Phe Asn Val Tyr Cys Phe Arg Asp Ser Ala Gln Pro Ser 350 355 360Ala Ile Pro Glu Ala Ser Asn Pro Ala Ser Asn Pro Ala Ser Asp 365 370 375Gly Leu Glu Ala Ile Val Thr Val Thr Glu Thr Leu Glu Glu Leu 380 385 390Gln Leu Pro Gln Glu Ala Thr Glu Ser Glu Ser Arg Gly Ala Ile 395 400 405Tyr Ser Ile Pro Ile Met Glu Asp Gly Gly Gly Gly Ser Ser Thr 410 415 420Pro Glu Asp Pro Ala Glu Ala Pro Arg Thr Leu Leu Glu Phe Glu 425 430 435Thr Gln Ser Met Val Pro Pro Thr Gly Phe Ser Glu Glu Glu Gly 440 445 450Lys Ala Leu Glu Glu Glu Glu Lys Tyr Glu Asp Glu Glu Glu Lys 455 460 465Glu Glu Glu Glu Glu Glu Glu Glu Val Glu Asp Glu Ala Leu Trp 470 475 480Ala Trp Pro Ser Glu Leu Ser Ser Pro Gly Pro Glu Ala Ser Leu 485 490 495Pro Thr Glu Pro Ala Ala Gln Glu Lys Ser Leu Ser Gln Ala Pro 500 505 510Ala Arg Ala Val Leu Gln Pro Gly Ala Ser Pro Leu Pro Asp Gly 515 520 525Glu Ser Glu Ala Ser Arg Pro Pro Arg Val His Gly Pro Pro Thr 530 535 540Glu Thr Leu Pro Thr Pro Arg Glu Arg Asn Leu Ala Ser Pro Ser 545 550 555Pro Ser Thr Leu Val Glu Ala Arg Glu Val Gly Glu Ala Thr Gly 560 565 570Gly Pro Glu Leu Ser Gly Val Pro Arg Gly Glu Ser Glu Glu Thr 575 580 585Gly Ser Ser Glu Gly Ala Pro Ser Leu Leu Pro Ala Thr Arg Ala 590 595 600Pro Glu Gly Thr Arg Glu Leu Glu Ala Pro Ser Glu Asp Asn Ser 605 610 615Gly Arg Thr Ala Pro Ala Gly Thr Ser Val Gln Ala Gln Pro Val 620 625 630Leu Pro Thr Asp Ser Ala Ser Arg Gly Gly Val Ala Val Val Pro 635 640 645Ala Ser Gly Asp Cys Val Pro Ser Pro Cys His Asn Gly Gly Thr 650 655 660Cys Leu Glu Glu Glu Glu Gly Val Arg Cys Leu Cys Leu Pro Gly 665 670 675Tyr Gly Gly Asp Leu Cys Asp Val Gly Leu Arg Phe Cys Asn Pro 680 685 690Gly Trp Asp Ala Phe Gln Gly Ala Cys Tyr Lys His Phe Ser Thr 695 700 705Arg Arg Ser Trp Glu Glu Ala Glu Thr Gln Cys Arg Met Tyr Gly 710 715 720Ala His Leu Ala Ser Ile Ser Thr Pro Glu Glu Gln Asp Phe Ile 725 730 735Asn Asn Arg Tyr Arg Glu Tyr Gln Trp Ile Gly Leu Asn Asp Arg 740 745 750Thr Ile Glu Gly Asp Phe Leu Trp Ser Asp Gly Val Pro Leu Leu 755 760 765Tyr Glu Asn Trp Asn Pro Gly Gln Pro Asp Ser Tyr Phe Leu Ser 770 775 780Gly Glu Asn Cys Val Val Met Val Trp His Asp Gln Gly Gln Trp 785 790 795Ser Asp Val Pro Cys Asn Tyr His Leu Ser Tyr Thr Cys Lys Met 800 805 810Gly Leu Val Ser Cys Gly Pro Pro Pro Glu Leu Pro Leu Ala Gln 815 820 825Val Phe Gly Arg Pro Arg Leu Arg Tyr Glu Val Asp Thr Val Leu 830 835 840Arg Tyr Arg Cys Arg Glu Gly Leu Ala Gln Arg Asn Leu Pro Leu 845 850 855Ile Arg Cys Gln Glu Asn Gly Arg Trp Glu Ala Pro Gln Ile Ser 860 865 870Cys Val Pro Arg Arg Pro Ala Arg Ala Leu His Pro Glu Glu Asp 875 880 885Pro Glu Gly Arg Gln Gly Arg Leu Leu Gly Arg Trp Lys Ala Leu 890 895 900Leu Ile Pro Pro Ser Ser Pro Met Pro Gly Pro 905 910 53 3316 DNA HomoSapien 53 ctgccaggtg acagccgcca agatggggtc ttgggccctg ctgtggcctc 50ccctgctgtt caccgggctg ctcgtccgac ccccggggac catggcccag 100 gcccagtactgctctgtgaa caaggacatc tttgaagtag aggagaacac 150 aaatgtcacc gagccgctggtggacatcca cgtcccggag ggccaggagg 200 tgaccctcgg agccttgtcc accccctttgcatttcggat ccagggaaac 250 cagctgtttc tcaacgtgac tcctgattac gaggagaagtcactgcttga 300 ggctcagctg ctgtgtcaga gcggaggcac attggtgacc cagctaaggg350 tgttcgtgtc agtgctggac gtcaatgaca atgcccccga attccccttt 400aagaccaagg agataagggt ggaggaggac acgaaagtga actccaccgt 450 catccctgagacgcaactgc aggctgagga ccgcgacaag gacgacattc 500 tgttctacac cctccaggaaatgacagcag gtgccagtga ctacttctcc 550 ctggtgagtg taaaccgtcc cgccctgaggctggaccggc ccctggactt 600 ctacgagcgg ccgaacatga ccttctggct gctggtgcgggacactccag 650 gggagaatgt ggaacccagc cacactgcca ccgccacact agtgctgaac700 gtggtgcccg ccgacctgcg gcccccgtgg ttcctgccct gcaccttctc 750agatggctac gtctgcattc aagctcagta ccacggggct gtccccacgg 800 ggcacatactgccatctccc ctcgtcctgc gtcccggacc catctacgct 850 gaggacggag accgcggcatcaaccagccc atcatctaca gcatctttag 900 gggaaacgtg aatggtacat tcatcatccacccagactcg ggcaacctca 950 ccgtggccag gagtgtcccc agccccatga ccttccttctgctggtgaag 1000 ggccaacagg ccgaccttgc ccgctactca gtgacccagg tcaccgtgga1050 ggctgtggct gcggccggga gcccgccccg cttcccccag agcctgtatc 1100gtggcaccgt ggcgcgtggc gctggagcgg gcgttgtggt caaggatgca 1150 gctgccccttctcagcctct gaggatccag gctcaggacc cggagttctc 1200 ggacctcaac tcggccatcacatatcgaat taccaaccac tcacacttcc 1250 ggatggaggg agaggttgtg ctgaccaccaccacactggc acaggcggga 1300 gccttctacg cagaggttga ggcccacaac acggtgacctctggcaccgc 1350 aaccacagtc attgagatac aagtttccga acaggagccc ccctccacag1400 aggctggagg aacaactggg ccctggacca gcaccacttc cgaggtcccc 1450agaccccctg agccctccca gggaccctcc acgaccagct ctgggggagg 1500 cacaggccctcatccaccct ctggcacaac tctgaggcca ccaacctcgt 1550 ccacacccgg ggggcccccgggtgcagaaa acagcacctc ccaccaacca 1600 gccactcccg gtggggacac agcacagaccccaaagccag gaacctctca 1650 gccgatgccc cccggtgtgg gaaccagcac ctcccaccaaccagccacac 1700 ccagtggggg cacagcacag accccagagc caggaacctc tcagccgatg1750 ccccccagta tgggaaccag cacctcccac caaccagcca cacccggtgg 1800gggcacagca cagaccccag aggcaggaac ctctcagccg atgccccccg 1850 gtatgggaaccagcacctcc caccaaccaa ccacacccgg tgggggcaca 1900 gcacagaccc cagagccaggaacctctcag ccgatgcccc tcagcaagag 1950 caccccatct tcaggtggcg gcccctcggaggacaagcgc ttctcggtgg 2000 tggatatggc ggccctgggc ggggtgctgg gtgcgctgctgctgctggct 2050 ctccttggcc tcgccgtcct tgtccacaag cactatggcc cccggctcaa2100 gtgctgctct ggcaaagctc cggagcccca gccccaaggc tttgacaacc 2150aggcgttcct ccctgaccac aaggccaact gggcgcccgt ccccagcccc 2200 acgcacgaccccaagcccgc ggaggcaccg atgcccgcag agcccgcacc 2250 ccccggccct gcctccccaggcggtgcccc tgagcccccc gcagcggccc 2300 gagctggcgg aagccccacg gcggtgaggtccatcctgac caaggagcgg 2350 cggccggagg gcgggtacaa ggccgtctgg tttggcgaggacatcgggac 2400 ggaggcagac gtggtcgttc tcaacgcgcc caccctggac gtggatggcg2450 ccagtgactc cggcagcggc gacgagggcg agggcgcggg gaggggtggg 2500ggtccctacg atgcacccgg tggtgatgac tcctacatct aagtggcccc 2550 tccaccctctcccccagccg cacgggcact ggaggtctcg ctcccccagc 2600 ctccgacccg aggcagaataaagcaaggct cccgaaaccc aggccatggc 2650 gtggggcagg cgcgtgggtc cctgggggccccattcactc agtcccctgt 2700 cgtcattagc gcttgagccc aggtgtgcag atgaggcggtgggtctggcc 2750 acgctgtccc caccccaagg ctgcagcact tcccgtaaac cacctgcagt2800 gcccgccgcc ttcccgaggc tctgtgccag ctagtctggg aagttcctct 2850cccgctctaa ccacagcccg aggggggctc ccctcccccg acctgcacca 2900 gagatctcaggcacccggct caactcagac ctcccgctcc cgaccctaca 2950 cagagattgc ctggggaggctgaggagccg atgcaaaccc ccaaggcgac 3000 gcacttggga gccggtggtc tcaaacacctgccgggggtc ctagtcccct 3050 tctgaaatct acatgcttgg gttggagcgc agcagtaaacaccctgccca 3100 gtgacctgga ctgaggcgcg ctgggggtgg gtgcgccgtg tggcctgagc3150 aggagccaga ccaggaggcc taggggtgag agacacattc ccctcgctgc 3200tcccaaagcc agagcccagg ctgggcgccc atgcccagaa ccatcaaggg 3250 atcccttgcggcttgtcagc actttcccta atggaaatac accattaatt 3300 cctttccaaa tgtttt 331654 839 PRT Homo Sapien 54 Met Gly Ser Trp Ala Leu Leu Trp Pro Pro LeuLeu Phe Thr Gly 1 5 10 15 Leu Leu Val Arg Pro Pro Gly Thr Met Ala GlnAla Gln Tyr Cys 20 25 30 Ser Val Asn Lys Asp Ile Phe Glu Val Glu Glu AsnThr Asn Val 35 40 45 Thr Glu Pro Leu Val Asp Ile His Val Pro Glu Gly GlnGlu Val 50 55 60 Thr Leu Gly Ala Leu Ser Thr Pro Phe Ala Phe Arg Ile GlnGly 65 70 75 Asn Gln Leu Phe Leu Asn Val Thr Pro Asp Tyr Glu Glu Lys Ser80 85 90 Leu Leu Glu Ala Gln Leu Leu Cys Gln Ser Gly Gly Thr Leu Val 95100 105 Thr Gln Leu Arg Val Phe Val Ser Val Leu Asp Val Asn Asp Asn 110115 120 Ala Pro Glu Phe Pro Phe Lys Thr Lys Glu Ile Arg Val Glu Glu 125130 135 Asp Thr Lys Val Asn Ser Thr Val Ile Pro Glu Thr Gln Leu Gln 140145 150 Ala Glu Asp Arg Asp Lys Asp Asp Ile Leu Phe Tyr Thr Leu Gln 155160 165 Glu Met Thr Ala Gly Ala Ser Asp Tyr Phe Ser Leu Val Ser Val 170175 180 Asn Arg Pro Ala Leu Arg Leu Asp Arg Pro Leu Asp Phe Tyr Glu 185190 195 Arg Pro Asn Met Thr Phe Trp Leu Leu Val Arg Asp Thr Pro Gly 200205 210 Glu Asn Val Glu Pro Ser His Thr Ala Thr Ala Thr Leu Val Leu 215220 225 Asn Val Val Pro Ala Asp Leu Arg Pro Pro Trp Phe Leu Pro Cys 230235 240 Thr Phe Ser Asp Gly Tyr Val Cys Ile Gln Ala Gln Tyr His Gly 245250 255 Ala Val Pro Thr Gly His Ile Leu Pro Ser Pro Leu Val Leu Arg 260265 270 Pro Gly Pro Ile Tyr Ala Glu Asp Gly Asp Arg Gly Ile Asn Gln 275280 285 Pro Ile Ile Tyr Ser Ile Phe Arg Gly Asn Val Asn Gly Thr Phe 290295 300 Ile Ile His Pro Asp Ser Gly Asn Leu Thr Val Ala Arg Ser Val 305310 315 Pro Ser Pro Met Thr Phe Leu Leu Leu Val Lys Gly Gln Gln Ala 320325 330 Asp Leu Ala Arg Tyr Ser Val Thr Gln Val Thr Val Glu Ala Val 335340 345 Ala Ala Ala Gly Ser Pro Pro Arg Phe Pro Gln Ser Leu Tyr Arg 350355 360 Gly Thr Val Ala Arg Gly Ala Gly Ala Gly Val Val Val Lys Asp 365370 375 Ala Ala Ala Pro Ser Gln Pro Leu Arg Ile Gln Ala Gln Asp Pro 380385 390 Glu Phe Ser Asp Leu Asn Ser Ala Ile Thr Tyr Arg Ile Thr Asn 395400 405 His Ser His Phe Arg Met Glu Gly Glu Val Val Leu Thr Thr Thr 410415 420 Thr Leu Ala Gln Ala Gly Ala Phe Tyr Ala Glu Val Glu Ala His 425430 435 Asn Thr Val Thr Ser Gly Thr Ala Thr Thr Val Ile Glu Ile Gln 440445 450 Val Ser Glu Gln Glu Pro Pro Ser Thr Glu Ala Gly Gly Thr Thr 455460 465 Gly Pro Trp Thr Ser Thr Thr Ser Glu Val Pro Arg Pro Pro Glu 470475 480 Pro Ser Gln Gly Pro Ser Thr Thr Ser Ser Gly Gly Gly Thr Gly 485490 495 Pro His Pro Pro Ser Gly Thr Thr Leu Arg Pro Pro Thr Ser Ser 500505 510 Thr Pro Gly Gly Pro Pro Gly Ala Glu Asn Ser Thr Ser His Gln 515520 525 Pro Ala Thr Pro Gly Gly Asp Thr Ala Gln Thr Pro Lys Pro Gly 530535 540 Thr Ser Gln Pro Met Pro Pro Gly Val Gly Thr Ser Thr Ser His 545550 555 Gln Pro Ala Thr Pro Ser Gly Gly Thr Ala Gln Thr Pro Glu Pro 560565 570 Gly Thr Ser Gln Pro Met Pro Pro Ser Met Gly Thr Ser Thr Ser 575580 585 His Gln Pro Ala Thr Pro Gly Gly Gly Thr Ala Gln Thr Pro Glu 590595 600 Ala Gly Thr Ser Gln Pro Met Pro Pro Gly Met Gly Thr Ser Thr 605610 615 Ser His Gln Pro Thr Thr Pro Gly Gly Gly Thr Ala Gln Thr Pro 620625 630 Glu Pro Gly Thr Ser Gln Pro Met Pro Leu Ser Lys Ser Thr Pro 635640 645 Ser Ser Gly Gly Gly Pro Ser Glu Asp Lys Arg Phe Ser Val Val 650655 660 Asp Met Ala Ala Leu Gly Gly Val Leu Gly Ala Leu Leu Leu Leu 665670 675 Ala Leu Leu Gly Leu Ala Val Leu Val His Lys His Tyr Gly Pro 680685 690 Arg Leu Lys Cys Cys Ser Gly Lys Ala Pro Glu Pro Gln Pro Gln 695700 705 Gly Phe Asp Asn Gln Ala Phe Leu Pro Asp His Lys Ala Asn Trp 710715 720 Ala Pro Val Pro Ser Pro Thr His Asp Pro Lys Pro Ala Glu Ala 725730 735 Pro Met Pro Ala Glu Pro Ala Pro Pro Gly Pro Ala Ser Pro Gly 740745 750 Gly Ala Pro Glu Pro Pro Ala Ala Ala Arg Ala Gly Gly Ser Pro 755760 765 Thr Ala Val Arg Ser Ile Leu Thr Lys Glu Arg Arg Pro Glu Gly 770775 780 Gly Tyr Lys Ala Val Trp Phe Gly Glu Asp Ile Gly Thr Glu Ala 785790 795 Asp Val Val Val Leu Asn Ala Pro Thr Leu Asp Val Asp Gly Ala 800805 810 Ser Asp Ser Gly Ser Gly Asp Glu Gly Glu Gly Ala Gly Arg Gly 815820 825 Gly Gly Pro Tyr Asp Ala Pro Gly Gly Asp Asp Ser Tyr Ile 830 83555 3846 DNA Homo Sapien 55 gcagctgggt tctcccggtt cccttgggca ggtgcagggtcgggttcaaa 50 gcctccggaa cgcgttttgg cctgatttga ggaggggggc ggggagggac 100ctgcggcttg cggccccgcc cccttctccg gctcgcagcc gaccggtaag 150 cccgcctcctccctcggccg gccctggggc cgtgtccgcc gggcaactcc 200 agccgaggcc tgggcttctgcctgcaggtg tctgcggcga ggcccctagg 250 gtacagcccg atttggcccc atggtgggtttcggggccaa ccggcgggct 300 ggccgcctgc cctctctcgt gctggtggtg ctgctggtggtgatcgtcgt 350 cctcgccttc aactactgga gcatctcctc ccgccacgtc ctgcttcagg400 aggaggtggc cgagctgcag ggccaggtcc agcgcaccga agtggcccgc 450gggcggctgg aaaagcgcaa ttcggacctc ttgctgttgg tggacacgca 500 caagaaacagatcgaccaga aggaggccga ctacggccgc ctcagcagcc 550 ggctgcaggc cagagagggcctcgggaaga gatgcgagga tgacaaggtt 600 aaactacaga acaacatatc gtatcagatggcagacatac atcatttaaa 650 ggagcaactt gctgagcttc gtcaggaatt tcttcgacaagaagaccagc 700 ttcaggacta taggaagaac aatacttacc ttgtgaagag gttagaatat750 gaaagttttc agtgtggaca gcagatgaag gaattgagag cacagcatga 800agaaaatatt aaaaagttag cagaccagtt tttagaggaa caaaagcaag 850 agacccaaaagattcaatca aatgatggaa aggaattgga tataaacaat 900 caagtagtac ctaaaaatattccaaaagta gctgagaatg ttgcagataa 950 gaatgaagaa ccctcaagca atcatattccacatgggaaa gaacaaatca 1000 aaagaggtgg tgatgcaggg atgcctggaa tagaagagaatgacctagca 1050 aaagttgatg atcttccccc tgctttaagg aagcctccta tttcagtttc1100 tcaacatgaa agtcatcaag caatctccca tcttccaact ggacaacctc 1150tctccccaaa tatgcctcca gattcacaca taaaccacaa tggaaacccc 1200 ggtacttcaaaacagaatcc ttccagtcct cttcagcgtt taattccagg 1250 ctcaaacttg gacagtgaacccagaattca aacagatata ctaaagcagg 1300 ctaccaagga cagagtcagt gatttccataaattgaagca aaatgatgaa 1350 gaacgagagc ttcaaatgga tcctgcagac tatggaaagcaacatttcaa 1400 tgatgtcctt taagtcctaa aggaatgctt cagaaaacct aaagtgctgt1450 aaaatgaaat cattctactt tgtcctttct gacttttgtt gtaaagacga 1500attgtatcag ttgtaaagat acattgagat agaattaagg aaaaacttta 1550 atgaaggaatgtacccatgt acatatgtga actttttcat attgtattat 1600 caaggtatag acttttttggttatgataca gttaagccaa aaacagctaa 1650 tctttgcatc taaagcaaac taatgtatatttcacatttt attgagccga 1700 cttatttcca caaatagata aacaggacaa aatagttgtacaggttatat 1750 gtggcatagc ataaccacag taagaacaga acagatattc agcagaaaac1800 tttttatact ctaattcttt tttttttttt tttgagacag agttttagtc 1850ttgtttccca ggctggagtg caatggcaca atcttggctc actgcaacct 1900 ccgcctcctgggttcaggca attttcctgc ctcagcctcc caagtagctg 1950 ggattacagg cacccaccaccatgcccagc taatttttgt atttttaata 2000 gagagctaat aattgtatat ttaataaagacgggtttcac catgttggcc 2050 aggctggtct tgaactcctg acctcaggtg atcctcctgcattggcctcc 2100 caaagtgctg gaattccagg catgagccac tgcgcccagt ctacacacta2150 attcttgtta gcccaacagc tgttctgttc tatctacccc tcatttcacg 2200ctcaaggagt catacctaga atagttacac acaagaggga aactggaagc 2250 caaacactgtacagtattgt gtagaaagtc acctccctac tccttttatt 2300 ttacatgagt gctgatgtgttttggcagat gagctttcag ctgaggcctg 2350 atggaaattg agataacctg caaagacataacagtattta tgagttatat 2400 cttagttctt gaaattgtgg aatgcatgat tgacaatatatttttaattt 2450 ttattttttc aagtaatacc agtactgttt aactatagcc agaactggct2500 aaaattttta tattttcaga gttgaagttg gtgaagacat tcatgattta 2550aacaccagat cctgaaaggg gttaaatcta ctttgaaatg aatctgcaat 2600 cagtatttcaaagcttttct ggtaatttta gtgatcttat ttgattagac 2650 tttttcagaa gtactaaataaggaatttta acaggttttt attaatgcac 2700 agataaatag aagtacagtg aggtctatagccattttatt aaaatagctt 2750 aaaagtttgt aaaaaaatga atctttgtaa ttacttaatatgttagttaa 2800 gaacccgtca agcttatatt tgctagactt acaaattatt ttaaatgcat2850 ttatcttttt tgacactatt cagtggaatg tgtaagctag ctaattcttg 2900ttttctgatt taaagcactt ttaaatctta tcctgccccc taaaaacaaa 2950 aggttttgatcacaagggga aatttaagat tgttaaccct gtttttcaga 3000 agggctactg ttaattgcacataaacatga aatgtgtttt cccctgtgta 3050 ctaacacatt ctaggcaaaa ttcaaacttatagtggtaaa gaaacaggtt 3100 gttcacttgc tgaggtgcaa aaattcttaa gacttctgtttgaaattgct 3150 caatgactag gaaaagatgt agtagtttac taaaattgtt tttctaccat3200 atcaaattaa acaattcatg cctttatagg gtcaggccta caatgaatag 3250gtatggtggt ttcacagaat tttaaaatag agttaaaggg aagtgatgta 3300 catttcgggggcattagggt agggagatga atcaaaaaat acccctagta 3350 atgctttata ttttaatactgcaaaagctt tacaaatgga aaccatgcaa 3400 ttacctgcct tagttctttt gtcataaaaacaatcacttg gttggttgta 3450 ttgtagctat tacttataca gcaacatttc ttcaattagcagtctagaca 3500 ttttataaac agaaatcttg gaccaattga taatatttct gactgtatta3550 atattttagt gctataaaat actatgtgaa tctcttaaaa atctgacatt 3600ttacagtctg tattagacat actgttttta taatgtttta cttctgcctt 3650 aagatttaggttttttaaat gtatttttgc cctgaattaa gtgttaattt 3700 gatggaaact ctgcttttaaaatcatcatt tactgggttc taataaatta 3750 aaaattaaac ttgaaaaaaa aaaaaaaaaaaaaaaaaaaa aaaaaaaaaa 3800 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaaaaaaaa 3846 56 380 PRT Homo Sapien 56 Met Val Gly Phe Gly Ala Asn ArgArg Ala Gly Arg Leu Pro Ser 1 5 10 15 Leu Val Leu Val Val Leu Leu ValVal Ile Val Val Leu Ala Phe 20 25 30 Asn Tyr Trp Ser Ile Ser Ser Arg HisVal Leu Leu Gln Glu Glu 35 40 45 Val Ala Glu Leu Gln Gly Gln Val Gln ArgThr Glu Val Ala Arg 50 55 60 Gly Arg Leu Glu Lys Arg Asn Ser Asp Leu LeuLeu Leu Val Asp 65 70 75 Thr His Lys Lys Gln Ile Asp Gln Lys Glu Ala AspTyr Gly Arg 80 85 90 Leu Ser Ser Arg Leu Gln Ala Arg Glu Gly Leu Gly LysArg Cys 95 100 105 Glu Asp Asp Lys Val Lys Leu Gln Asn Asn Ile Ser TyrGln Met 110 115 120 Ala Asp Ile His His Leu Lys Glu Gln Leu Ala Glu LeuArg Gln 125 130 135 Glu Phe Leu Arg Gln Glu Asp Gln Leu Gln Asp Tyr ArgLys Asn 140 145 150 Asn Thr Tyr Leu Val Lys Arg Leu Glu Tyr Glu Ser PheGln Cys 155 160 165 Gly Gln Gln Met Lys Glu Leu Arg Ala Gln His Glu GluAsn Ile 170 175 180 Lys Lys Leu Ala Asp Gln Phe Leu Glu Glu Gln Lys GlnGlu Thr 185 190 195 Gln Lys Ile Gln Ser Asn Asp Gly Lys Glu Leu Asp IleAsn Asn 200 205 210 Gln Val Val Pro Lys Asn Ile Pro Lys Val Ala Glu AsnVal Ala 215 220 225 Asp Lys Asn Glu Glu Pro Ser Ser Asn His Ile Pro HisGly Lys 230 235 240 Glu Gln Ile Lys Arg Gly Gly Asp Ala Gly Met Pro GlyIle Glu 245 250 255 Glu Asn Asp Leu Ala Lys Val Asp Asp Leu Pro Pro AlaLeu Arg 260 265 270 Lys Pro Pro Ile Ser Val Ser Gln His Glu Ser His GlnAla Ile 275 280 285 Ser His Leu Pro Thr Gly Gln Pro Leu Ser Pro Asn MetPro Pro 290 295 300 Asp Ser His Ile Asn His Asn Gly Asn Pro Gly Thr SerLys Gln 305 310 315 Asn Pro Ser Ser Pro Leu Gln Arg Leu Ile Pro Gly SerAsn Leu 320 325 330 Asp Ser Glu Pro Arg Ile Gln Thr Asp Ile Leu Lys GlnAla Thr 335 340 345 Lys Asp Arg Val Ser Asp Phe His Lys Leu Lys Gln AsnAsp Glu 350 355 360 Glu Arg Glu Leu Gln Met Asp Pro Ala Asp Tyr Gly LysGln His 365 370 375 Phe Asn Asp Val Leu 380 57 841 DNA Homo Sapien 57ggatgggcga gcagtctgaa tgccagaatg gataaccgtt ttgctacagc 50 atttgtaattgcttgtgtgc ttagcctcat ttccaccatc tacatggcag 100 cctccattgg cacagacttctggtatgaat atcgaagtcc agttcaagaa 150 aattccagtg atttgaataa aagcatctgggatgaattca ttagtgatga 200 ggcagatgaa aagacttata atgatgcact ttttcgatacaatggcacag 250 tgggattgtg gagacggtgt atcaccatac ccaaaaacat gcattggtat300 agcccaccag aaaggacaga gtcatttgat gtggtcacaa aatgtgtgag 350tttcacacta actgagcagt tcatggagaa atttgttgat cccggaaacc 400 acaatagcgggattgatctc cttaggacct atctttggcg ttgccagttc 450 cttttacctt ttgtgagtttaggtttgatg tgctttgggg ctttgatcgg 500 actttgtgct tgcatttgcc gaagcttatatcccaccatt gccacgggca 550 ttctccatct ccttgcagat accatgctgt gaagtccaggccacatggag 600 gtgtcctgtg tagatgctcc agctgaaatc ccaagctaag ctcccaactg650 acagccaaca tcatttccag ccatgtgtgg gagccatcct ggatgtccag 700ccttaacaag ccttcagagg acttcagcca cagctattat cttactacat 750 ccttgtgagactctaataaa gaaccaacta gctgagccca atcaacctat 800 ggaactgata gaaataaaatgaattgttgt tttgtgccgt t 841 58 184 PRT Homo Sapien 58 Met Asp Asn ArgPhe Ala Thr Ala Phe Val Ile Ala Cys Val Leu 1 5 10 15 Ser Leu Ile SerThr Ile Tyr Met Ala Ala Ser Ile Gly Thr Asp 20 25 30 Phe Trp Tyr Glu TyrArg Ser Pro Val Gln Glu Asn Ser Ser Asp 35 40 45 Leu Asn Lys Ser Ile TrpAsp Glu Phe Ile Ser Asp Glu Ala Asp 50 55 60 Glu Lys Thr Tyr Asn Asp AlaLeu Phe Arg Tyr Asn Gly Thr Val 65 70 75 Gly Leu Trp Arg Arg Cys Ile ThrIle Pro Lys Asn Met His Trp 80 85 90 Tyr Ser Pro Pro Glu Arg Thr Glu SerPhe Asp Val Val Thr Lys 95 100 105 Cys Val Ser Phe Thr Leu Thr Glu GlnPhe Met Glu Lys Phe Val 110 115 120 Asp Pro Gly Asn His Asn Ser Gly IleAsp Leu Leu Arg Thr Tyr 125 130 135 Leu Trp Arg Cys Gln Phe Leu Leu ProPhe Val Ser Leu Gly Leu 140 145 150 Met Cys Phe Gly Ala Leu Ile Gly LeuCys Ala Cys Ile Cys Arg 155 160 165 Ser Leu Tyr Pro Thr Ile Ala Thr GlyIle Leu His Leu Leu Ala 170 175 180 Asp Thr Met Leu 59 997 DNA HomoSapien 59 gcgtggacac cacctcagcc cactgagcag gagtcacagc acgaagacca 50agcgcaaagc gacccctgcc ctccatcctg actgctcctc ctaagagaga 100 tggcaccggccagagcagga ttctgccccc ttctgctgct tctgctgctg 150 gggctgtggg tggcagagatcccagtcagt gccaagccca agggcatgac 200 ctcatcacag tggtttaaaa ttcagcacatgcagcccagc cctcaagcat 250 gcaactcagc catgaaaaac attaacaagc acacaaaacggtgcaaagac 300 ctcaacacct tcctgcacga gcctttctcc agtgtggccg ccacctgcca350 gacccccaaa atagcctgca agaatggcga taaaaactgc caccagagcc 400acgggcccgt gtccctgacc atgtgtaagc tcacctcagg gaagtatccg 450 aactgcaggtacaaagagaa gcgacagaac aagtcttacg tagtggcctg 500 taagcctccc cagaaaaaggactctcagca attccacctg gttcctgtac 550 acttggacag agtcctttag gtttccagactggcttgctc tttggctgac 600 cttcaattcc ctctccagga ctccgcacca ctcccctacacccagagcat 650 tctcttcccc tcatctcttg gggctgttcc tggttcagcc tctgctggga700 ggctgaagct gacactctgg tgagctgagc tctagaggga tggcttttca 750tctttttgtt gctgttttcc cagatgctta tccccaagaa acagcaagct 800 caggtctgtgggttccctgg tctatgccat tgcacatgtc tcccctgccc 850 cctggcatta gggcagcatgacaaggagag gaaataaatg gaaagggggc 900 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaaaaaaaaaaaa aaaaaaaaaa 950 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaaaaaaaaa 997 60 156 PRT Homo Sapien 60 Met Ala Pro Ala Arg Ala Gly PheCys Pro Leu Leu Leu Leu Leu 1 5 10 15 Leu Leu Gly Leu Trp Val Ala GluIle Pro Val Ser Ala Lys Pro 20 25 30 Lys Gly Met Thr Ser Ser Gln Trp PheLys Ile Gln His Met Gln 35 40 45 Pro Ser Pro Gln Ala Cys Asn Ser Ala MetLys Asn Ile Asn Lys 50 55 60 His Thr Lys Arg Cys Lys Asp Leu Asn Thr PheLeu His Glu Pro 65 70 75 Phe Ser Ser Val Ala Ala Thr Cys Gln Thr Pro LysIle Ala Cys 80 85 90 Lys Asn Gly Asp Lys Asn Cys His Gln Ser His Gly ProVal Ser 95 100 105 Leu Thr Met Cys Lys Leu Thr Ser Gly Lys Tyr Pro AsnCys Arg 110 115 120 Tyr Lys Glu Lys Arg Gln Asn Lys Ser Tyr Val Val AlaCys Lys 125 130 135 Pro Pro Gln Lys Lys Asp Ser Gln Gln Phe His Leu ValPro Val 140 145 150 His Leu Asp Arg Val Leu 155 61 520 DNA Homo Sapien61 cgggtcatgc gccgccgcct gtggctgggc ctggcctggc tgctgctggc 50 gcgggcgccggacgccgcgg gaaccccgag cgcgtcgcgg ggaccgcgca 100 gctacccgca cctggagggcgacgtgcgct ggcggcgcct cttctcctcc 150 actcacttct tcctgcgcgt ggatcccggcggccgcgtgc agggcacccg 200 ctggcgccac ggccaggaca gcatcctgga gatccgctctgtacacgtgg 250 gcgtcgtggt catcaaagca gtgtcctcag gcttctacgt ggccatgaac300 cgccggggcc gcctctacgg gtcgcgactc tacaccgtgg actgcaggtt 350ccgggagcgc atcgaagaga acggccacaa cacctacgcc tcacagcgct 400 ggcgccgccgcggccagccc atgttcctgg cgctggacag gagggggggg 450 ccccggccag gcggccggacgcggcggtac cacctgtccg cccacttcct 500 gcccgtcctg gtctcctgag 520 62 170PRT Homo Sapien 62 Met Arg Arg Arg Leu Trp Leu Gly Leu Ala Trp Leu LeuLeu Ala 1 5 10 15 Arg Ala Pro Asp Ala Ala Gly Thr Pro Ser Ala Ser ArgGly Pro 20 25 30 Arg Ser Tyr Pro His Leu Glu Gly Asp Val Arg Trp Arg ArgLeu 35 40 45 Phe Ser Ser Thr His Phe Phe Leu Arg Val Asp Pro Gly Gly Arg50 55 60 Val Gln Gly Thr Arg Trp Arg His Gly Gln Asp Ser Ile Leu Glu 6570 75 Ile Arg Ser Val His Val Gly Val Val Val Ile Lys Ala Val Ser 80 8590 Ser Gly Phe Tyr Val Ala Met Asn Arg Arg Gly Arg Leu Tyr Gly 95 100105 Ser Arg Leu Tyr Thr Val Asp Cys Arg Phe Arg Glu Arg Ile Glu 110 115120 Glu Asn Gly His Asn Thr Tyr Ala Ser Gln Arg Trp Arg Arg Arg 125 130135 Gly Gln Pro Met Phe Leu Ala Leu Asp Arg Arg Gly Gly Pro Arg 140 145150 Pro Gly Gly Arg Thr Arg Arg Tyr His Leu Ser Ala His Phe Leu 155 160165 Pro Val Leu Val Ser 170 63 2329 DNA Homo Sapien 63 atccctcgacctcgacccac gcgtccgctg gaaggtggcg tgccctcctc 50 tggctggtac catgcagctcccactggccc tgtgtctcgt ctgcctgctg 100 gtacacacag ccttccgtgt agtggagggccaggggtggc aggcgttcaa 150 gaatgatgcc acggaaatca tccccgagct cggagagtaccccgagcctc 200 caccggagct ggagaacaac aagaccatga accgggcgga gaacggaggg250 cggcctcccc accacccctt tgagaccaaa gacgtgtccg agtacagctg 300ccgcgagctg cacttcaccc gctacgtgac cgatgggccg tgccgcagcg 350 ccaagccggtcaccgagctg gtgtgctccg gccagtgcgg cccggcgcgc 400 ctgctgccca acgccatcggccgcggcaag tggtggcgac ctagtgggcc 450 cgacttccgc tgcatccccg accgctaccgcgcgcagcgc gtgcagctgc 500 tgtgtcccgg tggtgaggcg ccgcgcgcgc gcaaggtgcgcctggtggcc 550 tcgtgcaagt gcaagcgcct cacccgcttc cacaaccagt cggagctcaa600 ggacttcggg accgaggccg ctcggccgca gaagggccgg aagccgcggc 650cccgcgcccg gagcgccaaa gccaaccagg ccgagctgga gaacgcctac 700 tagagcccgcccgcgcccct ccccaccggc gggcgccccg gccctgaacc 750 cgcgccccac atttctgtcctctgcgcgtg gtttgattgt ttatatttca 800 ttgtaaatgc ctgcaaccca gggcagggggctgagacctt ccaggccctg 850 aggaatcccg ggcgccggca aggcccccct cagcccgccagctgaggggt 900 cccacggggc aggggaggga attgagagtc acagacactg agccacgcag950 ccccgcctct ggggccgcct acctttgctg gtcccacttc agaggaggca 1000gaaatggaag cattttcacc gccctggggt tttaagggag cggtgtggga 1050 gtgggaaagtccagggactg gttaagaaag ttggataaga ttcccccttg 1100 cacctcgctg cccatcagaaagcctgaggc gtgcccagag cacaagactg 1150 ggggcaactg tagatgtggt ttctagtcctggctctgcca ctaacttcct 1200 gtgtaacctt gaactacaca attctccttc gggacctcaatttccacttt 1250 gtaaaatgag ggtggaggtg ggaataggat ctcgaggaga ctattggcat1300 atgattccaa ggactccagt gccttttgaa tgggcagagg tgagagagag 1350agagagaaag agagagaatg aatgcagttg cattgattca gtgccaaggt 1400 cacttccagaattcagagtt gtgatgctct cttctgacag ccaaagatga 1450 aaaacaaaca gaaaaaaaaaagtaaagagt ctatttatgg ctgacatatt 1500 tacggctgac aaactcctgg aagaagctatgctgcttccc agcctggctt 1550 ccccggatgt ttggctacct ccacccctcc atctcaaagaaataacatca 1600 tccattgggg tagaaaagga gagggtccga gggtggtggg agggatagaa1650 atcacatccg ccccaacttc ccaaagagca gcatccctcc cccgacccat 1700agccatgttt taaagtcacc ttccgaagag aagtgaaagg ttcaaggaca 1750 ctggccttgcaggcccgagg gagcagccat cacaaactca cagaccagca 1800 catccctttt gagacaccgccttctgccca ccactcacgg acacatttct 1850 gcctagaaaa cagcttctta ctgctcttacatgtgatggc atatcttaca 1900 ctaaaagaat attattgggg gaaaaactac aagtgctgtacatatgctga 1950 gaaactgcag agcataatag ctgccaccca aaaatctttt tgaaaatcat2000 ttccagacaa cctcttactt tctgtgtagt ttttaattgt taaaaaaaaa 2050aagttttaaa cagaagcaca tgacatatga aagcctgcag gactggtcgt 2100 ttttttggcaattcttccac gtgggacttg tccacaagaa tgaaagtagt 2150 ggtttttaaa gagttaagttacatatttat tttctcactt aagttattta 2200 tgcaaaagtt tttcttgtag agaatgacaatgttaatatt gctttatgaa 2250 ttaacagtct gttcttccag agtccagaga cattgttaataaagacaatg 2300 aatcatgaaa aaaaaaaaaa aaaaaaaaa 2329 64 213 PRT HomoSapien 64 Met Gln Leu Pro Leu Ala Leu Cys Leu Val Cys Leu Leu Val His 15 10 15 Thr Ala Phe Arg Val Val Glu Gly Gln Gly Trp Gln Ala Phe Lys 2025 30 Asn Asp Ala Thr Glu Ile Ile Pro Glu Leu Gly Glu Tyr Pro Glu 35 4045 Pro Pro Pro Glu Leu Glu Asn Asn Lys Thr Met Asn Arg Ala Glu 50 55 60Asn Gly Gly Arg Pro Pro His His Pro Phe Glu Thr Lys Asp Val 65 70 75 SerGlu Tyr Ser Cys Arg Glu Leu His Phe Thr Arg Tyr Val Thr 80 85 90 Asp GlyPro Cys Arg Ser Ala Lys Pro Val Thr Glu Leu Val Cys 95 100 105 Ser GlyGln Cys Gly Pro Ala Arg Leu Leu Pro Asn Ala Ile Gly 110 115 120 Arg GlyLys Trp Trp Arg Pro Ser Gly Pro Asp Phe Arg Cys Ile 125 130 135 Pro AspArg Tyr Arg Ala Gln Arg Val Gln Leu Leu Cys Pro Gly 140 145 150 Gly GluAla Pro Arg Ala Arg Lys Val Arg Leu Val Ala Ser Cys 155 160 165 Lys CysLys Arg Leu Thr Arg Phe His Asn Gln Ser Glu Leu Lys 170 175 180 Asp PheGly Thr Glu Ala Ala Arg Pro Gln Lys Gly Arg Lys Pro 185 190 195 Arg ProArg Ala Arg Ser Ala Lys Ala Asn Gln Ala Glu Leu Glu 200 205 210 Asn AlaTyr 65 2663 DNA Homo Sapien 65 cccactcggc ggtttggcgg gagggaggggctttgcgcag gccccgctcc 50 cgccccgcct ccatgcggcc cgccccgatt gcgctgtggctgcgcctggt 100 cttggccctg gcccttgtcc gcccccgggc tgtggggtgg gccccggtcc150 gagcccccat ctatgtcagc agctgggccg tccaggtgtc ccagggtaac 200cgggaggtcg agcgcctggc acgcaaattc ggcttcgtca acctggggcc 250 gatcttctctgacgggcagt actttcacct gcggcaccgg ggcgtggtcc 300 agcagtccct gaccccgcactggggccacc gcctgcacct gaagaaaaac 350 cccaaggtgc agtggttcca gcagcagacgctgcagcggc gggtgaaacg 400 ctctgtcgtg gtgcccacgg acccctggtt ctccaagcagtggtacatga 450 acagcgaggc ccaaccagac ctgagcatcc tgcaggcctg gagtcagggg500 ctgtcaggcc agggcatcgt ggtctctgtg ctggacgatg gcatcgagaa 550ggaccacccg gacctctggg ccaactacga ccccctggcc agctatgact 600 tcaatgactacgacccggac ccccagcccc gctacacccc cagcaaagag 650 aaccggcacg ggacccgctgtgctggggag gtggccgcga tggccaacaa 700 tggcttctgt ggtgtggggg tcgctttcaacgcccgaatc ggaggcgtac 750 ggatgctgga cggtaccatc accgatgtca tcgaggcccagtcgctgagc 800 ctgcagccgc agcacatcca catttacagc gccagctggg gtcccgagga850 cgacggccgc acggtggacg gccccggcat cctcacccgc gaggccttcc 900ggcgtggtgt gaccaagggc cgcggcgggc tgggcacgct cttcatctgg 950 gcctcgggcaacggcggcct gcactacgac aactgcaact gcgacggcta 1000 caccaacagc atccacacgctttccgtggg cagcaccacc cagcagggcc 1050 gcgtgccctg gtacagcgaa gcctgcgcctccaccctcac caccacctac 1100 agcagcggcg tggccaccga cccccagatc gtcaccacggacctgcatca 1150 cgggtgcaca gaccagcaca cgggcacctc ggcctcagcc ccactggcgg1200 ccggcatgat cgccctagcg ctggaggcca acccgttcct gacgtggaga 1250gacatgcagc acctggtggt ccgcgcgtcc aagccggcgc acctgcaggc 1300 cgaggactggaggaccaacg gcgtggggcg ccaagtgagc catcactacg 1350 gatacgggct gctggacgccgggctgctgg tggacaccgc ccgcacctgg 1400 ctgcccaccc agccgcagag gaagtgcgccgtccgggtcc agagccgccc 1450 cacccccatc ctgccgctga tctacatcag ggaaaacgtatcggcctgcg 1500 ccggcctcca caactccatc cgctcgctgg agcacgtgca ggcgcagctg1550 acgctgtcct acagccggcg cggagacctg gagatctcgc tcaccagccc 1600catgggcacg cgctccacac tcgtggccat acgacccttg gacgtcagca 1650 ctgaaggctacaacaactgg gtcttcatgt ccacccactt ctgggatgag 1700 aacccacagg gcgtgtggaccctgggccta gagaacaagg gctactattt 1750 caacacgggg acgttgtacc gctacacgctgctgctctat gggacggccg 1800 aggacatgac agcgcggcct acaggccccc aggtgaccagcagcgcgtgt 1850 gtgcagcggg acacagaggg gctgtgccag gcgtgtgacg gccccgccta1900 catcctggga cagctctgcc tggcctactg ccccccgcgg ttcttcaacc 1950acacaaggct ggtgaccgct gggcctgggc acacggcggc gcccgcgctg 2000 agggtctgctccagctgcca tgcctcctgc tacacctgcc gcggcggctc 2050 cccgagggac tgcacctcctgtcccccatc ctccacgctg gaccagcagc 2100 agggctcctg catgggaccc accacccccgacagccgccc ccggcttaga 2150 gctgccgcct gtccccacca ccgctgccca gcctcggccatggtgctgag 2200 cctcctggcc gtgaccctcg gaggccccgt cctctgcggc atgtccatgg2250 acctcccact atacgcctgg ctctcccgtg ccagggccac ccccaccaaa 2300ccccaggtct ggctgccagc tggaacctga agttgtcagc tcagaaagcg 2350 accttgcccccgcctgggtc cctgacaggc actgctgcca tgctgcctcc 2400 ccaggctggc cccagaggagcgagcaccag cacccgacgc ctggcctgcc 2450 agggatgggc cccgtggaac cccgaagcctggcgggagag agagagagag 2500 aagtctcctc tgcattttgg gtttgggcag gagtgggctggggggagagg 2550 ctggagcacc ccaaaagcca ggggaaagtg gagggagaga aacgtgacac2600 tgtccgtctc gggcaccgcg tccaacctca gagtttgcaa ataaaggttg 2650cttagaaggt gaa 2663 66 755 PRT Homo Sapien 66 Met Arg Pro Ala Pro IleAla Leu Trp Leu Arg Leu Val Leu Ala 1 5 10 15 Leu Ala Leu Val Arg ProArg Ala Val Gly Trp Ala Pro Val Arg 20 25 30 Ala Pro Ile Tyr Val Ser SerTrp Ala Val Gln Val Ser Gln Gly 35 40 45 Asn Arg Glu Val Glu Arg Leu AlaArg Lys Phe Gly Phe Val Asn 50 55 60 Leu Gly Pro Ile Phe Ser Asp Gly GlnTyr Phe His Leu Arg His 65 70 75 Arg Gly Val Val Gln Gln Ser Leu Thr ProHis Trp Gly His Arg 80 85 90 Leu His Leu Lys Lys Asn Pro Lys Val Gln TrpPhe Gln Gln Gln 95 100 105 Thr Leu Gln Arg Arg Val Lys Arg Ser Val ValVal Pro Thr Asp 110 115 120 Pro Trp Phe Ser Lys Gln Trp Tyr Met Asn SerGlu Ala Gln Pro 125 130 135 Asp Leu Ser Ile Leu Gln Ala Trp Ser Gln GlyLeu Ser Gly Gln 140 145 150 Gly Ile Val Val Ser Val Leu Asp Asp Gly IleGlu Lys Asp His 155 160 165 Pro Asp Leu Trp Ala Asn Tyr Asp Pro Leu AlaSer Tyr Asp Phe 170 175 180 Asn Asp Tyr Asp Pro Asp Pro Gln Pro Arg TyrThr Pro Ser Lys 185 190 195 Glu Asn Arg His Gly Thr Arg Cys Ala Gly GluVal Ala Ala Met 200 205 210 Ala Asn Asn Gly Phe Cys Gly Val Gly Val AlaPhe Asn Ala Arg 215 220 225 Ile Gly Gly Val Arg Met Leu Asp Gly Thr IleThr Asp Val Ile 230 235 240 Glu Ala Gln Ser Leu Ser Leu Gln Pro Gln HisIle His Ile Tyr 245 250 255 Ser Ala Ser Trp Gly Pro Glu Asp Asp Gly ArgThr Val Asp Gly 260 265 270 Pro Gly Ile Leu Thr Arg Glu Ala Phe Arg ArgGly Val Thr Lys 275 280 285 Gly Arg Gly Gly Leu Gly Thr Leu Phe Ile TrpAla Ser Gly Asn 290 295 300 Gly Gly Leu His Tyr Asp Asn Cys Asn Cys AspGly Tyr Thr Asn 305 310 315 Ser Ile His Thr Leu Ser Val Gly Ser Thr ThrGln Gln Gly Arg 320 325 330 Val Pro Trp Tyr Ser Glu Ala Cys Ala Ser ThrLeu Thr Thr Thr 335 340 345 Tyr Ser Ser Gly Val Ala Thr Asp Pro Gln IleVal Thr Thr Asp 350 355 360 Leu His His Gly Cys Thr Asp Gln His Thr GlyThr Ser Ala Ser 365 370 375 Ala Pro Leu Ala Ala Gly Met Ile Ala Leu AlaLeu Glu Ala Asn 380 385 390 Pro Phe Leu Thr Trp Arg Asp Met Gln His LeuVal Val Arg Ala 395 400 405 Ser Lys Pro Ala His Leu Gln Ala Glu Asp TrpArg Thr Asn Gly 410 415 420 Val Gly Arg Gln Val Ser His His Tyr Gly TyrGly Leu Leu Asp 425 430 435 Ala Gly Leu Leu Val Asp Thr Ala Arg Thr TrpLeu Pro Thr Gln 440 445 450 Pro Gln Arg Lys Cys Ala Val Arg Val Gln SerArg Pro Thr Pro 455 460 465 Ile Leu Pro Leu Ile Tyr Ile Arg Glu Asn ValSer Ala Cys Ala 470 475 480 Gly Leu His Asn Ser Ile Arg Ser Leu Glu HisVal Gln Ala Gln 485 490 495 Leu Thr Leu Ser Tyr Ser Arg Arg Gly Asp LeuGlu Ile Ser Leu 500 505 510 Thr Ser Pro Met Gly Thr Arg Ser Thr Leu ValAla Ile Arg Pro 515 520 525 Leu Asp Val Ser Thr Glu Gly Tyr Asn Asn TrpVal Phe Met Ser 530 535 540 Thr His Phe Trp Asp Glu Asn Pro Gln Gly ValTrp Thr Leu Gly 545 550 555 Leu Glu Asn Lys Gly Tyr Tyr Phe Asn Thr GlyThr Leu Tyr Arg 560 565 570 Tyr Thr Leu Leu Leu Tyr Gly Thr Ala Glu AspMet Thr Ala Arg 575 580 585 Pro Thr Gly Pro Gln Val Thr Ser Ser Ala CysVal Gln Arg Asp 590 595 600 Thr Glu Gly Leu Cys Gln Ala Cys Asp Gly ProAla Tyr Ile Leu 605 610 615 Gly Gln Leu Cys Leu Ala Tyr Cys Pro Pro ArgPhe Phe Asn His 620 625 630 Thr Arg Leu Val Thr Ala Gly Pro Gly His ThrAla Ala Pro Ala 635 640 645 Leu Arg Val Cys Ser Ser Cys His Ala Ser CysTyr Thr Cys Arg 650 655 660 Gly Gly Ser Pro Arg Asp Cys Thr Ser Cys ProPro Ser Ser Thr 665 670 675 Leu Asp Gln Gln Gln Gly Ser Cys Met Gly ProThr Thr Pro Asp 680 685 690 Ser Arg Pro Arg Leu Arg Ala Ala Ala Cys ProHis His Arg Cys 695 700 705 Pro Ala Ser Ala Met Val Leu Ser Leu Leu AlaVal Thr Leu Gly 710 715 720 Gly Pro Val Leu Cys Gly Met Ser Met Asp LeuPro Leu Tyr Ala 725 730 735 Trp Leu Ser Arg Ala Arg Ala Thr Pro Thr LysPro Gln Val Trp 740 745 750 Leu Pro Ala Gly Thr 755 67 332 DNA HomoSapien 67 atgaggaagc tccagggcag gatggtttac ctgcctggac agcaagatga 50tggctacact agcccccatt ctctgggcgc ctggatttgc ccaccagatc 100 tcctcacctcttgcccttca cctcctgctg tacctacaag gtctccccga 150 ttctcatctg cccataatcatggacacagc cccaggatgt gcaggactct 200 cagggaccat ctggagttcc agctggaatctgggcctggt ggagtgggag 250 tggggcaggg gcctgcattg ggctgactta gagagcacagttattccatc 300 catatggaaa taaacatttt ggattcctga tc 332 68 88 PRT HomoSapien 68 Met Met Ala Thr Leu Ala Pro Ile Leu Trp Ala Pro Gly Phe Ala 15 10 15 His Gln Ile Ser Ser Pro Leu Ala Leu His Leu Leu Leu Tyr Leu 2025 30 Gln Gly Leu Pro Asp Ser His Leu Pro Ile Ile Met Asp Thr Ala 35 4045 Pro Gly Cys Ala Gly Leu Ser Gly Thr Ile Trp Ser Ser Ser Trp 50 55 60Asn Leu Gly Leu Val Glu Trp Glu Trp Gly Arg Gly Leu His Trp 65 70 75 AlaAsp Leu Glu Ser Thr Val Ile Pro Ser Ile Trp Lys 80 85 69 1302 DNA HomoSapien unsure 1218-1253 unknown base 69 tttgcagtgg ggtcctcctc tggcctcctgcccctcctgc tgctgctgct 50 gcttccattg ctggcagccc agggtggggg tggcctgcaggcagcgctgc 100 tggcccttga ggtggggctg gtgggtctgg gggcctccta cctgctcctt150 tgtacagccc tgcacctgcc ctccagtctt ttcctactcc tggcccaggg 200taccgcactg ggggccgtcc tgggcctgag ctggcgccga ggcctcatgg 250 gtgttcccctgggccttgga gctgcctggc tcttagcttg gccaggccta 300 gctctacctc tggtggctatggcagcgggg ggcagatggg tgcggcagca 350 gggcccccgg gtgcgccggg gcatatctcgactctggttg cgggttctgc 400 tgcgcctgtc acccatggcc ttccgggccc tgcagggctgtggggctgtg 450 ggggaccggg gtctgtttgc actgtacccc aaaaccaaca aggatggctt500 ccgcagccgc ctgcccgtcc ctgggccccg gcggcgtaat ccccgcacca 550cccaacaccc attagctctg ttggcaaggg tctgggtcct gtgcaagggc 600 tggaactggcgtctggcacg ggccagccag ggtttagcat cccacttgcc 650 cccgtgggcc atccacacactggccagctg gggcctgctt cggggtgaac 700 ggcccacccg aatcccccgg ctactaccacgcagccagcg ccagctaggg 750 ccccctgcct cccgccagcc actgccaggg actctagccgggcggaggtc 800 acgcacccgc cagtcccggg ccctgccccc ctggaggtag ctgactccag850 cccttccagc ccaaatctag agcattgagc actttatctc ccacgactca 900gtgaagtttc tccagtccct agtcctctct tttcacccac cttcctcagt 950 ttgctcacttaccccaggcc cagcccttcg gacctctaga caggcagcct 1000 cctcagctgt ggagtccagcagtcactctg tgttctcctg gcgctcctcc 1050 cctaagttat tgctgttcgc ccgctgtgtgtgctcatcct caccctcatt 1100 gactcaggcc tggggccagg ggtggtggag ggtgggaagagtcatgtttt 1150 ttttctcctc tttgattttg tttttctgtc tcccttccaa cctgtcccct1200 tccccccacc aaaaaaannn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1250nnnaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1300 aa 1302 70197 PRT Homo Sapien 70 Met Gly Val Pro Leu Gly Leu Gly Ala Ala Trp LeuLeu Ala Trp 1 5 10 15 Pro Gly Leu Ala Leu Pro Leu Val Ala Met Ala AlaGly Gly Arg 20 25 30 Trp Val Arg Gln Gln Gly Pro Arg Val Arg Arg Gly IleSer Arg 35 40 45 Leu Trp Leu Arg Val Leu Leu Arg Leu Ser Pro Met Ala PheArg 50 55 60 Ala Leu Gln Gly Cys Gly Ala Val Gly Asp Arg Gly Leu Phe Ala65 70 75 Leu Tyr Pro Lys Thr Asn Lys Asp Gly Phe Arg Ser Arg Leu Pro 8085 90 Val Pro Gly Pro Arg Arg Arg Asn Pro Arg Thr Thr Gln His Pro 95 100105 Leu Ala Leu Leu Ala Arg Val Trp Val Leu Cys Lys Gly Trp Asn 110 115120 Trp Arg Leu Ala Arg Ala Ser Gln Gly Leu Ala Ser His Leu Pro 125 130135 Pro Trp Ala Ile His Thr Leu Ala Ser Trp Gly Leu Leu Arg Gly 140 145150 Glu Arg Pro Thr Arg Ile Pro Arg Leu Leu Pro Arg Ser Gln Arg 155 160165 Gln Leu Gly Pro Pro Ala Ser Arg Gln Pro Leu Pro Gly Thr Leu 170 175180 Ala Gly Arg Arg Ser Arg Thr Arg Gln Ser Arg Ala Leu Pro Pro 185 190195 Trp Arg 71 1976 DNA Homo Sapien 71 gtttgggggt tgtttgggat tagtgaagctactgcctttg ccgccagcgc 50 agcctcagag tttgattatt tgcaatgtca ggctttgaaaacttaaacac 100 ggatttctac cagacaagtt acagcatcga tgatcagtca cagcagtcct150 atgattatgg aggaagtgga ggaccctata gcaaacagta tgctggctat 200gactattcgc agcaaggcag atttgtccct ccagacatga tgcagccaca 250 acagccatacaccgggcaga tttaccagcc aactcaggca tatactccag 300 cttcacctca gcctttctatggaaacaact ttgaggatga gccaccttta 350 ttagaagagt taggtatcaa ttttgaccacatctggcaaa aaacactaac 400 agtattacat ccgttaaaag tagcagatgg cagcatcatgaatgaaactg 450 atttggcagg tccaatggtt ttttgccttg cttttggagc cacattgcta500 ctggctggca aaatccagtt tggctatgta tacgggatca gtgcaattgg 550atgtctagga atgttttgtt tattaaactt aatgagtatg acaggtgttt 600 catttggttgtgtggcaagt gtccttggat attgtcttct gcccatgatc 650 ctactttcca gctttgcagtgatattttct ttgcaaggaa tggtaggaat 700 cattctcact gctgggatta ttggatggtgtagtttttct gcttccaaaa 750 tatttatttc tgcattagcc atggaaggac agcaacttttagtagcatat 800 ccttgcgctt tgttatatgg agtctttgcc ctgatttccg tcttttgaaa850 atttatctgg gatgtggaca tcagtgggcc agatgtacaa aaaggacctt 900gaactcttaa attggaccag caaactgctg cagcgcaact ctcatgcaga 950 tttacatttgactgttggag caatgaaagt aaacgtgtat ctcttgttca 1000 tttttataga acttttgcatactatattgg atttacctgc ggtgtgacta 1050 gctttaaatg tttgtgttta tacagataagaaatgctatt tctttctggt 1100 tcctgcagcc attgaaaaac ctttttcctt gcaaattataatgtttttga 1150 tagattttta tcaactgtgg gaaaccaaac acaaagctga taacctttct1200 taaaaacgac ccagtcacag taaagaagac acaagacggc cgggcgtggt 1250agctcacgcc tgtaatccca gcactttggg aggccgaggc gggcggatca 1300 caagggcaggagatcgagac catcctggtt aacacggtga aaccccgact 1350 ctactaaaac tacaaaaaaaattagctggg cgtggtggcg ggcgcctgta 1400 gtcccagcta ctcaggaggc tgaggcaggagaagtgtgaa cccaggaggc 1450 ggagcttgca gtgagccgag atcacaccac tgcactccatccagcctggg 1500 tgacagggtg agactctgtc tcaaaaaaaa aaaaaaaagg agacacaaga1550 cttactgcaa aaatattttt ccaaggattt aggaaagaaa aattgccttg 1600tattctcaag tcaggtaact caaagcaaaa aagtgatcca aatgtagagt 1650 atgagtttgcactccaaaaa tttgacatta ctgtaaatta tctcatggaa 1700 tttttgctaa aattcagagatacgggaagt tcacaatcta cctcattgta 1750 gacatgaaat gcgaacactt acttacatattaatgttaac tcaaccttag 1800 ggacctggaa tggttgcatt aatgctataa tcgttggatcgccacatttc 1850 ccaaaaataa taaaaaaatc actaaccttt tttaaggaaa atatttaaag1900 ttttacaaaa ttcaatattg caattatcaa tgtaaagtac atttgaatgc 1950ttattaaaac tttcccaatt aatttt 1976 72 257 PRT Homo Sapien 72 Met Ser GlyPhe Glu Asn Leu Asn Thr Asp Phe Tyr Gln Thr Ser 1 5 10 15 Tyr Ser IleAsp Asp Gln Ser Gln Gln Ser Tyr Asp Tyr Gly Gly 20 25 30 Ser Gly Gly ProTyr Ser Lys Gln Tyr Ala Gly Tyr Asp Tyr Ser 35 40 45 Gln Gln Gly Arg PheVal Pro Pro Asp Met Met Gln Pro Gln Gln 50 55 60 Pro Tyr Thr Gly Gln IleTyr Gln Pro Thr Gln Ala Tyr Thr Pro 65 70 75 Ala Ser Pro Gln Pro Phe TyrGly Asn Asn Phe Glu Asp Glu Pro 80 85 90 Pro Leu Leu Glu Glu Leu Gly IleAsn Phe Asp His Ile Trp Gln 95 100 105 Lys Thr Leu Thr Val Leu His ProLeu Lys Val Ala Asp Gly Ser 110 115 120 Ile Met Asn Glu Thr Asp Leu AlaGly Pro Met Val Phe Cys Leu 125 130 135 Ala Phe Gly Ala Thr Leu Leu LeuAla Gly Lys Ile Gln Phe Gly 140 145 150 Tyr Val Tyr Gly Ile Ser Ala IleGly Cys Leu Gly Met Phe Cys 155 160 165 Leu Leu Asn Leu Met Ser Met ThrGly Val Ser Phe Gly Cys Val 170 175 180 Ala Ser Val Leu Gly Tyr Cys LeuLeu Pro Met Ile Leu Leu Ser 185 190 195 Ser Phe Ala Val Ile Phe Ser LeuGln Gly Met Val Gly Ile Ile 200 205 210 Leu Thr Ala Gly Ile Ile Gly TrpCys Ser Phe Ser Ala Ser Lys 215 220 225 Ile Phe Ile Ser Ala Leu Ala MetGlu Gly Gln Gln Leu Leu Val 230 235 240 Ala Tyr Pro Cys Ala Leu Leu TyrGly Val Phe Ala Leu Ile Ser 245 250 255 Val Phe 73 1285 DNA Homo Sapien73 acactggcca aaacgcggct cgccctcggc tgcgctcggc tcccgcgggc 50 gctcggccccgagcccctcc tccccctacc cgccggccgg acagggagga 100 gccaatggct gggcctgccatccacaccgc tcccatgctg ttcctcgtcc 150 tcctgctgcc ccagctgagc ctggcaggcgcccttgcacc tgggacccct 200 gcccggaacc tccctgagaa tcacattgac ctcccaggcccagcgctgtg 250 gacgcctcag gccagccacc accgccggcg gggcccgggc aagaaggagt300 ggggcccagg cctgcccagc caggcccagg atggggctgt ggtcaccgcc 350accaggcagg cctccaggct gccagaggct gaggggctgc tgcctgagca 400 gagtcctgcaggcctgctgc aggacaagga cctgctcctg ggactggcat 450 tgccctaccc cgagaaggagaacagacctc caggttggga gaggaccagg 500 aaacgcagca gggagcacaa gagacgcagggacaggttga ggctgcacca 550 aggccgagcc ttggtccgag gtcccagctc cctgatgaagaaggcagagc 600 tctccgaagc ccaggtgctg gatgcagcca tggaggaatc ctccaccagc650 ctggcgccca ccatgttctt tctcaccacc tttgaggcag cacctgccac 700agaagagtcc ctgatcctgc ccgtcacctc cctgcggccc cagcaggcac 750 agcccaggtctgacggggag gtgatgccca cgctggacat ggccttgttc 800 gactggaccg attatgaagacttaaaacct gatggttggc cctctgcaaa 850 gaagaaagag aaacaccgcg gtaaactctccagtgatggt aacgaaacat 900 caccagccga aggggaacca tgcgaccatc accaagactgcctgccaggg 950 acttgctgcg acctgcggga gcatctctgc acaccccaca accgaggcct1000 caacaacaaa tgcttcgatg actgcatgtg tgtggaaggg ctgcgctgct 1050atgccaaatt ccaccggaac cgcagggtta cacggaggaa agggcgctgt 1100 gtggagcccgagacggccaa cggcgaccag ggatccttca tcaacgtcta 1150 gcggccccgc gggactggggactgagccca ggaggtttgc acaagccggg 1200 cgatttgttt gtaactagca gtgggagatcaagttgggga acagatggct 1250 gaggctgcag actcaggccc aggacactca acccc 128574 348 PRT Homo Sapien 74 Met Ala Gly Pro Ala Ile His Thr Ala Pro MetLeu Phe Leu Val 1 5 10 15 Leu Leu Leu Pro Gln Leu Ser Leu Ala Gly AlaLeu Ala Pro Gly 20 25 30 Thr Pro Ala Arg Asn Leu Pro Glu Asn His Ile AspLeu Pro Gly 35 40 45 Pro Ala Leu Trp Thr Pro Gln Ala Ser His His Arg ArgArg Gly 50 55 60 Pro Gly Lys Lys Glu Trp Gly Pro Gly Leu Pro Ser Gln AlaGln 65 70 75 Asp Gly Ala Val Val Thr Ala Thr Arg Gln Ala Ser Arg Leu Pro80 85 90 Glu Ala Glu Gly Leu Leu Pro Glu Gln Ser Pro Ala Gly Leu Leu 95100 105 Gln Asp Lys Asp Leu Leu Leu Gly Leu Ala Leu Pro Tyr Pro Glu 110115 120 Lys Glu Asn Arg Pro Pro Gly Trp Glu Arg Thr Arg Lys Arg Ser 125130 135 Arg Glu His Lys Arg Arg Arg Asp Arg Leu Arg Leu His Gln Gly 140145 150 Arg Ala Leu Val Arg Gly Pro Ser Ser Leu Met Lys Lys Ala Glu 155160 165 Leu Ser Glu Ala Gln Val Leu Asp Ala Ala Met Glu Glu Ser Ser 170175 180 Thr Ser Leu Ala Pro Thr Met Phe Phe Leu Thr Thr Phe Glu Ala 185190 195 Ala Pro Ala Thr Glu Glu Ser Leu Ile Leu Pro Val Thr Ser Leu 200205 210 Arg Pro Gln Gln Ala Gln Pro Arg Ser Asp Gly Glu Val Met Pro 215220 225 Thr Leu Asp Met Ala Leu Phe Asp Trp Thr Asp Tyr Glu Asp Leu 230235 240 Lys Pro Asp Gly Trp Pro Ser Ala Lys Lys Lys Glu Lys His Arg 245250 255 Gly Lys Leu Ser Ser Asp Gly Asn Glu Thr Ser Pro Ala Glu Gly 260265 270 Glu Pro Cys Asp His His Gln Asp Cys Leu Pro Gly Thr Cys Cys 275280 285 Asp Leu Arg Glu His Leu Cys Thr Pro His Asn Arg Gly Leu Asn 290295 300 Asn Lys Cys Phe Asp Asp Cys Met Cys Val Glu Gly Leu Arg Cys 305310 315 Tyr Ala Lys Phe His Arg Asn Arg Arg Val Thr Arg Arg Lys Gly 320325 330 Arg Cys Val Glu Pro Glu Thr Ala Asn Gly Asp Gln Gly Ser Phe 335340 345 Ile Asn Val 75 1868 DNA Homo Sapien 75 cagaagggca aaaacattgactgcctcaag gtctcaagca ccagtcttca 50 ccgcggaaag catgttgtgg ctgttccaatcgctcctgtt tgtcttctgc 100 tttggcccag ggaatgtagt ttcacaaagc agcttaaccccattgatggt 150 gaacgggatt ctgggggagt cagtaactct tcccctggag tttcctgcag200 gagagaaggt caacttcatc acttggcttt tcaatgaaac atctcttgcc 250ttcatagtac cccatgaaac caaaagtcca gaaatccacg tgactaatcc 300 gaaacagggaaagcgactga acttcaccca gtcctactcc ctgcaactca 350 gcaacctgaa gatggaagacacaggctctt acagagccca gatatccaca 400 aagacctctg caaagctgtc cagttacactctgaggatat taagacaact 450 gaggaacata caagttacca atcacagtca gctatttcagaatatgacct 500 gtgagctcca tctgacttgc tctgtggagg atgcagatga caatgtctca550 ttcagatggg aggccttggg aaacacactt tcaagtcagc caaacctcac 600tgtctcctgg gaccccagga tttccagtga acaggactac acctgcatag 650 cagagaatgctgtcagtaat ttatccttct ctgtctctgc ccagaagctt 700 tgcgaagatg ttaaaattcaatatacagat accaaaatga ttctgtttat 750 ggtttctggg atatgcatag tcttcggtttcatcatactg ctgttacttg 800 ttttgaggaa aagaagagat tccctatctt tgtctactcagcgaacacag 850 ggccccgcag agtccgcaag gaacctagag tatgtttcag tgtctccaac900 gaacaacact gtgtatgctt cagtcactca ttcaaacagg gaaacagaaa 950tctggacacc tagagaaaat gatactatca caatttactc cacaattaat 1000 cattccaaagagagtaaacc cactttttcc agggcaactg cccttgacaa 1050 tgtcgtgtaa gttgctgaaaggcctcagag gaattcggga atgacacgtc 1100 ttctgatccc atgagacaga acaaagaacaggaagcttgg ttcctgttgt 1150 tcctggcaac agaatttgaa tatctaggat aggatgatcacctccagtcc 1200 ttcggactta aacctgccta cctgagtcaa acacctaagg ataacatcat1250 ttccagcatg tggttcaaat aatattttcc aatccacttc aggccaaaac 1300atgctaaaga taacacacca gcacattgac tctctctttg ataactaagc 1350 aaatggaattatggttgaca gagagtttat gatccagaag acaaccactt 1400 ctctcctttt agaaagcagcaggattgact tattgagaaa taatgcagtg 1450 tgttggttac atgtgtagtc tctggagttggatgggccca tcctgataca 1500 agttgagcat cccttgtctg aaatgcttgg gattagaaatgtttcagatt 1550 tcaatttttt ttcagatttt ggaatatttg cattatattt agcggttgag1600 tatccaaatc caaaaatcca aaattcaaaa tgctccaata agcatttccc 1650ttgagtttca ttgatgtcga tgcagtgctc aaaatctcag attttggagc 1700 aatttggatattggattttt ggatttggga tgctcaactt gtacaatgtt 1750 tattagacac atctcctgggacatactgcc taaccttttg gagccttagt 1800 ctcccagact gaaaaaggaa gaggatggtattacatcagc tccattgttt 1850 gagccaagaa tctaagtc 1868 76 332 PRT HomoSapien 76 Met Leu Trp Leu Phe Gln Ser Leu Leu Phe Val Phe Cys Phe Gly 15 10 15 Pro Gly Asn Val Val Ser Gln Ser Ser Leu Thr Pro Leu Met Val 2025 30 Asn Gly Ile Leu Gly Glu Ser Val Thr Leu Pro Leu Glu Phe Pro 35 4045 Ala Gly Glu Lys Val Asn Phe Ile Thr Trp Leu Phe Asn Glu Thr 50 55 60Ser Leu Ala Phe Ile Val Pro His Glu Thr Lys Ser Pro Glu Ile 65 70 75 HisVal Thr Asn Pro Lys Gln Gly Lys Arg Leu Asn Phe Thr Gln 80 85 90 Ser TyrSer Leu Gln Leu Ser Asn Leu Lys Met Glu Asp Thr Gly 95 100 105 Ser TyrArg Ala Gln Ile Ser Thr Lys Thr Ser Ala Lys Leu Ser 110 115 120 Ser TyrThr Leu Arg Ile Leu Arg Gln Leu Arg Asn Ile Gln Val 125 130 135 Thr AsnHis Ser Gln Leu Phe Gln Asn Met Thr Cys Glu Leu His 140 145 150 Leu ThrCys Ser Val Glu Asp Ala Asp Asp Asn Val Ser Phe Arg 155 160 165 Trp GluAla Leu Gly Asn Thr Leu Ser Ser Gln Pro Asn Leu Thr 170 175 180 Val SerTrp Asp Pro Arg Ile Ser Ser Glu Gln Asp Tyr Thr Cys 185 190 195 Ile AlaGlu Asn Ala Val Ser Asn Leu Ser Phe Ser Val Ser Ala 200 205 210 Gln LysLeu Cys Glu Asp Val Lys Ile Gln Tyr Thr Asp Thr Lys 215 220 225 Met IleLeu Phe Met Val Ser Gly Ile Cys Ile Val Phe Gly Phe 230 235 240 Ile IleLeu Leu Leu Leu Val Leu Arg Lys Arg Arg Asp Ser Leu 245 250 255 Ser LeuSer Thr Gln Arg Thr Gln Gly Pro Ala Glu Ser Ala Arg 260 265 270 Asn LeuGlu Tyr Val Ser Val Ser Pro Thr Asn Asn Thr Val Tyr 275 280 285 Ala SerVal Thr His Ser Asn Arg Glu Thr Glu Ile Trp Thr Pro 290 295 300 Arg GluAsn Asp Thr Ile Thr Ile Tyr Ser Thr Ile Asn His Ser 305 310 315 Lys GluSer Lys Pro Thr Phe Ser Arg Ala Thr Ala Leu Asp Asn 320 325 330 Val Val77 3073 DNA Homo Sapien 77 gatccctcga cctcgaccca cgcgtccgct ctttaatgctttctttttaa 50 gagatcacct tctgacttct cacagaagag gttaactatt acctgtggga 100agtcagaagg tgatctcttt aatgctttct ttttaagaat ttttcaaatt 150 gagactaattgcagaggttc cagttgacca gcattcatag gaatgaagac 200 aaacacagag atggtgtgtctaagaaactt caaaaggtgt agacctcctg 250 actgaagcat attggattta tttaatttttttcactgtat ttctgtcctc 300 ctacaaggga aagtcatgat tacactaact gagctaaaatgcttagcaga 350 tgcccagtca tcttatcaca tcttaaaacc atggtgggac gtcttctggt400 attacatcac actgatcatg ctgctggtgg ccgtgctggc cggagctctc 450cagctgacgc agagcagggt tctgtgctgt cttccatgca aagtggaatt 500 tgacaatcactgtgccgtgc cttgggacat cctgaaagcc agcatgaaca 550 catcctctaa tcctgggacaccgcttccgc tccccctccg aattcagaat 600 gacctccacc gacagcagta ctcctatattgatgccgtct gttacgagaa 650 acagctccat tggtttgcaa agtttttccc ctatctggtgctcttgcaca 700 cgctcatctt tgcagcctgc agcaactttt ggcttcacta ccccagtacc750 agttccaggc tcgagcattt tgtggccatc cttcacaagt gcttcgattc 800tccatggacc acccgcgccc tttcagaaac agtggctgag cagtcagtga 850 ggcctctgaaactctccaag tccaagattt tgctttcgtc ctcagggtgt 900 tcagctgaca tagattccggcaaacagtca ttgccctacc cacagccagg 950 tttggagtca gctggtatag aaagcccaacttccagtggc ctggacaaga 1000 aggagggtga acaggccaaa gccatctttg aaaaagtgaaaagattccgc 1050 atgcatgtgg agcagaagga catcatttat agagtatatc tgaaacagat1100 aatagtcaaa gtcattttgt ttgtgctcat cataacttat gttccatatt 1150ttttaaccca catcactctt gaaatcgact gttcagttga tgtgcaggct 1200 tttacaggatataagcgcta ccagtgtgtc tattccttgg cagaaatctt 1250 taaggtcctg gcttcattttatgtcatttt ggttatactt tatggtctga 1300 cctcttccta cagcctgtgg tggatgctgaggagttccct gaagcaatat 1350 tcctttgagg cgttaagaga aaaaagcaac tacagtgacatccctgatgt 1400 caagaatgac tttgccttca tccttcatct ggctgatcag tatgatcctc1450 tttattccaa acgcttctcc atattcctat cagaggtcag tgagaacaaa 1500ctgaaacaga tcaacctcaa taatgaatgg acagttgaga aactgaaaag 1550 taagcttgtgaaaaatgccc aggacaagat agaactgcat ctttttatgc 1600 tcaacggtct tccagacaatgtctttgagt taactgaaat ggaagtgcta 1650 agcctggagc ttatcccaga ggtgaagctgccctctgcag tctcacagct 1700 ggtcaacctc aaggagcttc gtgtgtacca ttcatctctggtcgtagacc 1750 atcctgcact ggcctttcta gaggagaatt taaaaatcct ccgcctgaaa1800 tttactgaaa tgggaaaaat cccacgctgg gtatttcacc tcaagaatct 1850caaggaactt tatctttcgg gctgtgttct ccctgaacag ttgagtacta 1900 tgcagttggagggctttcag gacttaaaaa atctaaggac cctgtacttg 1950 aagagcagcc tctcccggatcccacaagtt gttacagacc tcctgccttc 2000 attgcagaaa ctgtcccttg ataatgagggaagcaaactg gttgtgttga 2050 acaacttgaa aaagatggtc aatctgaaaa gcctagaactgatcagctgt 2100 gacctggaac gcatcccaca ttccattttc agcctgaata atttgcatga2150 gttagaccta agggaaaata accttaaaac tgtggaagag attagctttc 2200agcatcttca gaatctttcc tgcttaaagt tgtggcacaa taacattgct 2250 tatattcctgcacagattgg ggcattatct aacctagagc agctctcttt 2300 ggaccataat aatattgagaatctgccctt gcagcttttc ctatgcacta 2350 aactacatta tttggatcta agctataaccacttgacctt cattccagaa 2400 gaaatccagt atctgagtaa tttgcagtac tttgctgtgaccaacaacaa 2450 tattgagatg ctaccagatg ggctgtttca gtgcaaaaag ctgcagtgtt2500 tacttttggg gaaaaatagc ttgatgaatt tgtcccctca tgtgggtgag 2550ctgtcaaacc ttactcatct ggagctcatt ggtaattacc tggaaacact 2600 tcctcctgaactagaaggat gtcagtccct aaaacggaac tgtctgattg 2650 ttgaggagaa cttgctcaatactcttcctc tccctgtaac agaacgttta 2700 cagacgtgct tagacaaatg ttgacttaaagaaaagagac ccgtgtttca 2750 aaatcatttt taaaagtatg ctcggccggg cgtggtggctcatgcctata 2800 atcccagcac tttgggaggc caagatgggc ggattgcttg aggtcaggag2850 ttcgagacca gtctggccaa cctggtgaaa ccccatctct gctaaaacta 2900caaaaaaatt agccaggcgt ggtggcgtgc gcctgtaatc ccagctactt 2950 gggaggctgacgcaggggaa ttgcttgaac cagggaggtg gaggttgcag 3000 tgagccgaga ttgtgccactgtacaccagc ctgggtgaca gagcaagact 3050 cttatctcaa aaaaaaaaaa aaa 3073 78802 PRT Homo Sapien 78 Met Ile Thr Leu Thr Glu Leu Lys Cys Leu Ala AspAla Gln Ser 1 5 10 15 Ser Tyr His Ile Leu Lys Pro Trp Trp Asp Val PheTrp Tyr Tyr 20 25 30 Ile Thr Leu Ile Met Leu Leu Val Ala Val Leu Ala GlyAla Leu 35 40 45 Gln Leu Thr Gln Ser Arg Val Leu Cys Cys Leu Pro Cys LysVal 50 55 60 Glu Phe Asp Asn His Cys Ala Val Pro Trp Asp Ile Leu Lys Ala65 70 75 Ser Met Asn Thr Ser Ser Asn Pro Gly Thr Pro Leu Pro Leu Pro 8085 90 Leu Arg Ile Gln Asn Asp Leu His Arg Gln Gln Tyr Ser Tyr Ile 95 100105 Asp Ala Val Cys Tyr Glu Lys Gln Leu His Trp Phe Ala Lys Phe 110 115120 Phe Pro Tyr Leu Val Leu Leu His Thr Leu Ile Phe Ala Ala Cys 125 130135 Ser Asn Phe Trp Leu His Tyr Pro Ser Thr Ser Ser Arg Leu Glu 140 145150 His Phe Val Ala Ile Leu His Lys Cys Phe Asp Ser Pro Trp Thr 155 160165 Thr Arg Ala Leu Ser Glu Thr Val Ala Glu Gln Ser Val Arg Pro 170 175180 Leu Lys Leu Ser Lys Ser Lys Ile Leu Leu Ser Ser Ser Gly Cys 185 190195 Ser Ala Asp Ile Asp Ser Gly Lys Gln Ser Leu Pro Tyr Pro Gln 200 205210 Pro Gly Leu Glu Ser Ala Gly Ile Glu Ser Pro Thr Ser Ser Gly 215 220225 Leu Asp Lys Lys Glu Gly Glu Gln Ala Lys Ala Ile Phe Glu Lys 230 235240 Val Lys Arg Phe Arg Met His Val Glu Gln Lys Asp Ile Ile Tyr 245 250255 Arg Val Tyr Leu Lys Gln Ile Ile Val Lys Val Ile Leu Phe Val 260 265270 Leu Ile Ile Thr Tyr Val Pro Tyr Phe Leu Thr His Ile Thr Leu 275 280285 Glu Ile Asp Cys Ser Val Asp Val Gln Ala Phe Thr Gly Tyr Lys 290 295300 Arg Tyr Gln Cys Val Tyr Ser Leu Ala Glu Ile Phe Lys Val Leu 305 310315 Ala Ser Phe Tyr Val Ile Leu Val Ile Leu Tyr Gly Leu Thr Ser 320 325330 Ser Tyr Ser Leu Trp Trp Met Leu Arg Ser Ser Leu Lys Gln Tyr 335 340345 Ser Phe Glu Ala Leu Arg Glu Lys Ser Asn Tyr Ser Asp Ile Pro 350 355360 Asp Val Lys Asn Asp Phe Ala Phe Ile Leu His Leu Ala Asp Gln 365 370375 Tyr Asp Pro Leu Tyr Ser Lys Arg Phe Ser Ile Phe Leu Ser Glu 380 385390 Val Ser Glu Asn Lys Leu Lys Gln Ile Asn Leu Asn Asn Glu Trp 395 400405 Thr Val Glu Lys Leu Lys Ser Lys Leu Val Lys Asn Ala Gln Asp 410 415420 Lys Ile Glu Leu His Leu Phe Met Leu Asn Gly Leu Pro Asp Asn 425 430435 Val Phe Glu Leu Thr Glu Met Glu Val Leu Ser Leu Glu Leu Ile 440 445450 Pro Glu Val Lys Leu Pro Ser Ala Val Ser Gln Leu Val Asn Leu 455 460465 Lys Glu Leu Arg Val Tyr His Ser Ser Leu Val Val Asp His Pro 470 475480 Ala Leu Ala Phe Leu Glu Glu Asn Leu Lys Ile Leu Arg Leu Lys 485 490495 Phe Thr Glu Met Gly Lys Ile Pro Arg Trp Val Phe His Leu Lys 500 505510 Asn Leu Lys Glu Leu Tyr Leu Ser Gly Cys Val Leu Pro Glu Gln 515 520525 Leu Ser Thr Met Gln Leu Glu Gly Phe Gln Asp Leu Lys Asn Leu 530 535540 Arg Thr Leu Tyr Leu Lys Ser Ser Leu Ser Arg Ile Pro Gln Val 545 550555 Val Thr Asp Leu Leu Pro Ser Leu Gln Lys Leu Ser Leu Asp Asn 560 565570 Glu Gly Ser Lys Leu Val Val Leu Asn Asn Leu Lys Lys Met Val 575 580585 Asn Leu Lys Ser Leu Glu Leu Ile Ser Cys Asp Leu Glu Arg Ile 590 595600 Pro His Ser Ile Phe Ser Leu Asn Asn Leu His Glu Leu Asp Leu 605 610615 Arg Glu Asn Asn Leu Lys Thr Val Glu Glu Ile Ser Phe Gln His 620 625630 Leu Gln Asn Leu Ser Cys Leu Lys Leu Trp His Asn Asn Ile Ala 635 640645 Tyr Ile Pro Ala Gln Ile Gly Ala Leu Ser Asn Leu Glu Gln Leu 650 655660 Ser Leu Asp His Asn Asn Ile Glu Asn Leu Pro Leu Gln Leu Phe 665 670675 Leu Cys Thr Lys Leu His Tyr Leu Asp Leu Ser Tyr Asn His Leu 680 685690 Thr Phe Ile Pro Glu Glu Ile Gln Tyr Leu Ser Asn Leu Gln Tyr 695 700705 Phe Ala Val Thr Asn Asn Asn Ile Glu Met Leu Pro Asp Gly Leu 710 715720 Phe Gln Cys Lys Lys Leu Gln Cys Leu Leu Leu Gly Lys Asn Ser 725 730735 Leu Met Asn Leu Ser Pro His Val Gly Glu Leu Ser Asn Leu Thr 740 745750 His Leu Glu Leu Ile Gly Asn Tyr Leu Glu Thr Leu Pro Pro Glu 755 760765 Leu Glu Gly Cys Gln Ser Leu Lys Arg Asn Cys Leu Ile Val Glu 770 775780 Glu Asn Leu Leu Asn Thr Leu Pro Leu Pro Val Thr Glu Arg Leu 785 790795 Gln Thr Cys Leu Asp Lys Cys 800 79 1504 DNA Homo Sapien 79cggacgcgtg ggccgcgctc cctcacggcc cctcggcggc gcccgtcgga 50 tccggcctctctctgcgccc cggggcgcgc cacctccccg ccggaggtgt 100 ccacgcgtcc ggccgtccatccgtccgtcc ctcctggggc cggcgctgac 150 catgcccagc ggctgccgct gcctgcatctcgtgtgcctg ttgtgcattc 200 tgggggctcc cggtcagcct gtccgagccg atgactgcagctcccactgt 250 gacctggccc acggctgctg tgcacctgac ggctcctgca ggtgtgaccc300 gggctgggag gggctgcact gtgagcgctg tgtgaggatg cctggctgcc 350agcacggtac ctgccaccag ccatggcagt gcatctgcca cagtggctgg 400 gcaggcaagttctgtgacaa agatgaacat atctgtacca cgcagtcccc 450 ctgccagaat ggaggccagtgcatgtatga cgggggcggt gagtaccatt 500 gtgtgtgctt accaggcttc catgggcgtgactgcgagcg caaggctgga 550 ccctgtgaac aggcaggctc cccatgccgc aatggcgggcagtgccagga 600 cgaccagggc tttgctctca acttcacgtg ccgctgcttg gtgggctttg650 tgggtgcccg ctgtgaggta aatgtggatg actgcctgat gcggccttgt 700gctaacggtg ccacctgcct tgacggcata aaccgcttct cctgcctctg 750 tcctgagggctttgctggac gcttctgcac catcaacctg gatgactgtg 800 ccagccgccc atgccagagaggggcccgct gtcgggaccg tgtccacgac 850 ttcgactgcc tctgccccag tggctatggtggcaagacct gtgagcttgt 900 cttacctgtc ccagaccccc caaccacagt ggacacccctctagggccca 950 cctcagctgt agtggtacct gctacggggc cagcccccca cagcgcaggg1000 gctggtctgc tgcggatctc agtgaaggag gtggtgcgga ggcaagaggc 1050tgggctaggt gagcctagct tggtggccct ggtggtgttt ggggccctca 1100 ctgctgccctggttctggct actgtgttgc tgaccctgag ggcctggcgc 1150 cggggtgtct gcccccctggaccctgttgc taccctgccc cacactatgc 1200 tccagcgtgc caggaccagg agtgtcaggttagcatgctg ccagcagggc 1250 tccccctgcc acgtgacttg ccccctgagc ctggaaagaccacagcactg 1300 tgatggaggt gggggctttc tggccccctt cctcacctct tccacccctc1350 agactggagt ggtccgttct caccaccctt cagcttgggt acacacacag 1400aggagacctc agcctcacac cagaaatatt atttttttaa tacacagaat 1450 gtaagatggaattttatcaa ataaaactat gaaaatgcaa aaaaaaaaaa 1500 aaaa 1504 80 383 PRTHomo Sapien 80 Met Pro Ser Gly Cys Arg Cys Leu His Leu Val Cys Leu LeuCys 1 5 10 15 Ile Leu Gly Ala Pro Gly Gln Pro Val Arg Ala Asp Asp CysSer 20 25 30 Ser His Cys Asp Leu Ala His Gly Cys Cys Ala Pro Asp Gly Ser35 40 45 Cys Arg Cys Asp Pro Gly Trp Glu Gly Leu His Cys Glu Arg Cys 5055 60 Val Arg Met Pro Gly Cys Gln His Gly Thr Cys His Gln Pro Trp 65 7075 Gln Cys Ile Cys His Ser Gly Trp Ala Gly Lys Phe Cys Asp Lys 80 85 90Asp Glu His Ile Cys Thr Thr Gln Ser Pro Cys Gln Asn Gly Gly 95 100 105Gln Cys Met Tyr Asp Gly Gly Gly Glu Tyr His Cys Val Cys Leu 110 115 120Pro Gly Phe His Gly Arg Asp Cys Glu Arg Lys Ala Gly Pro Cys 125 130 135Glu Gln Ala Gly Ser Pro Cys Arg Asn Gly Gly Gln Cys Gln Asp 140 145 150Asp Gln Gly Phe Ala Leu Asn Phe Thr Cys Arg Cys Leu Val Gly 155 160 165Phe Val Gly Ala Arg Cys Glu Val Asn Val Asp Asp Cys Leu Met 170 175 180Arg Pro Cys Ala Asn Gly Ala Thr Cys Leu Asp Gly Ile Asn Arg 185 190 195Phe Ser Cys Leu Cys Pro Glu Gly Phe Ala Gly Arg Phe Cys Thr 200 205 210Ile Asn Leu Asp Asp Cys Ala Ser Arg Pro Cys Gln Arg Gly Ala 215 220 225Arg Cys Arg Asp Arg Val His Asp Phe Asp Cys Leu Cys Pro Ser 230 235 240Gly Tyr Gly Gly Lys Thr Cys Glu Leu Val Leu Pro Val Pro Asp 245 250 255Pro Pro Thr Thr Val Asp Thr Pro Leu Gly Pro Thr Ser Ala Val 260 265 270Val Val Pro Ala Thr Gly Pro Ala Pro His Ser Ala Gly Ala Gly 275 280 285Leu Leu Arg Ile Ser Val Lys Glu Val Val Arg Arg Gln Glu Ala 290 295 300Gly Leu Gly Glu Pro Ser Leu Val Ala Leu Val Val Phe Gly Ala 305 310 315Leu Thr Ala Ala Leu Val Leu Ala Thr Val Leu Leu Thr Leu Arg 320 325 330Ala Trp Arg Arg Gly Val Cys Pro Pro Gly Pro Cys Cys Tyr Pro 335 340 345Ala Pro His Tyr Ala Pro Ala Cys Gln Asp Gln Glu Cys Gln Val 350 355 360Ser Met Leu Pro Ala Gly Leu Pro Leu Pro Arg Asp Leu Pro Pro 365 370 375Glu Pro Gly Lys Thr Thr Ala Leu 380 81 1034 DNA Homo Sapien 81gtttgttgct caaaccgagt tctggagaac gccatcagct cgctgcttaa 50 aattaaaccacaggttccat tatgggtcga cttgatggga aagtcatcat 100 cctgacggcc gctgctcaggggattggcca agcagctgcc ttagcttttg 150 caagagaagg tgccaaagtc atagccacagacattaatga gtccaaactt 200 caggaactgg aaaagtaccc gggtattcaa actcgtgtccttgatgtcac 250 aaagaagaaa caaattgatc agtttgccag tgaagttgag agacttgatg300 ttctctttaa tgttgctggt tttgtccatc atggaactgt cctggattgt 350gaggagaaag actgggactt ctcgatgaat ctcaatgtgc gcagcatgta 400 cctgatgatcaaggcattcc ttcctaaaat gcttgctcag aaatctggca 450 atattatcaa catgtcttctgtggcttcca gcgtcaaagg agttgtgaac 500 agatgtgtgt acagcacaac caaggcagccgtgattggcc tcacaaaatc 550 tctggctgca gatttcatcc agcagggcat caggtgcaactgtgtgtgcc 600 caggaacagt tgatacgcca tctctacaag aaagaataca agccagagga650 aatcctgaag aggcacggaa tgatttcctg aagagacaaa agacgggaag 700attcgcaact gcagaagaaa tagccatgct ctgcgtgtat ttggcttctg 750 atgaatctgcttatgtaact ggtaaccctg tcatcattga tggaggctgg 800 agcttgtgat tttaggatctccatggtggg aaggaaggca ggcccttcct 850 atccacagtg aacctggtta cgaagaaaactcaccaatca tctccttcct 900 gttaatcaca tgttaatgaa aataagctct ttttaatgatgtcactgttt 950 gcaagagtct gattctttaa gtatattaat ctctttgtaa tctcttctga1000 aatcattgta aagaaataaa aatattgaac tcat 1034 82 245 PRT Homo Sapien82 Met Gly Arg Leu Asp Gly Lys Val Ile Ile Leu Thr Ala Ala Ala 1 5 10 15Gln Gly Ile Gly Gln Ala Ala Ala Leu Ala Phe Ala Arg Glu Gly 20 25 30 AlaLys Val Ile Ala Thr Asp Ile Asn Glu Ser Lys Leu Gln Glu 35 40 45 Leu GluLys Tyr Pro Gly Ile Gln Thr Arg Val Leu Asp Val Thr 50 55 60 Lys Lys LysGln Ile Asp Gln Phe Ala Ser Glu Val Glu Arg Leu 65 70 75 Asp Val Leu PheAsn Val Ala Gly Phe Val His His Gly Thr Val 80 85 90 Leu Asp Cys Glu GluLys Asp Trp Asp Phe Ser Met Asn Leu Asn 95 100 105 Val Arg Ser Met TyrLeu Met Ile Lys Ala Phe Leu Pro Lys Met 110 115 120 Leu Ala Gln Lys SerGly Asn Ile Ile Asn Met Ser Ser Val Ala 125 130 135 Ser Ser Val Lys GlyVal Val Asn Arg Cys Val Tyr Ser Thr Thr 140 145 150 Lys Ala Ala Val IleGly Leu Thr Lys Ser Leu Ala Ala Asp Phe 155 160 165 Ile Gln Gln Gly IleArg Cys Asn Cys Val Cys Pro Gly Thr Val 170 175 180 Asp Thr Pro Ser LeuGln Glu Arg Ile Gln Ala Arg Gly Asn Pro 185 190 195 Glu Glu Ala Arg AsnAsp Phe Leu Lys Arg Gln Lys Thr Gly Arg 200 205 210 Phe Ala Thr Ala GluGlu Ile Ala Met Leu Cys Val Tyr Leu Ala 215 220 225 Ser Asp Glu Ser AlaTyr Val Thr Gly Asn Pro Val Ile Ile Asp 230 235 240 Gly Gly Trp Ser Leu245 83 1961 DNA Homo Sapien 83 gggcggcggc ggcagcggtt ggaggttgtaggaccggcga ggaataggaa 50 tcatggcggc tgcgctgttc gtgctgctgg gattcgcgctgctgggcacc 100 cacggagcct ccggggctgc cggcttcgtc caggcgccgc tgtcccagca150 gaggtgggtg gggggcagtg tggagctgca ctgcgaggcc gtgggcagcc 200cggtgcccga gatccagtgg tggtttgaag ggcagggtcc caacgacacc 250 tgctcccagctctgggacgg cgcccggctg gaccgcgtcc acatccacgc 300 cacctaccac cagcacgcggccagcaccat ctccatcgac acgctcgtgg 350 aggaggacac gggcacttac gagtgccgggccagcaacga cccggatcgc 400 aaccacctga cccgggcgcc cagggtcaag tgggtccgcgcccaggcagt 450 cgtgctagtc ctggaacccg gcacagtctt cactaccgta gaagaccttg500 gctccaagat actcctcacc tgctccttga atgacagcgc cacagaggtc 550acagggcacc gctggctgaa ggggggcgtg gtgctgaagg aggacgcgct 600 gcccggccagaaaacggagt tcaaggtgga ctccgacgac cagtggggag 650 agtactcctg cgtcttcctccccgagccca tgggcacggc caacatccag 700 ctccacgggc ctcccagagt gaaggctgtgaagtcgtcag aacacatcaa 750 cgagggggag acggccatgc tggtctgcaa gtcagagtccgtgccacctg 800 tcactgactg ggcctggtac aagatcactg actctgagga caaggccctc850 atgaacggct ccgagagcag gttcttcgtg agttcctcgc agggccggtc 900agagctacac attgagaacc tgaacatgga ggccgacccc ggccagtacc 950 ggtgcaacggcaccagctcc aagggctccg accaggccat catcacgctc 1000 cgcgtgcgca gccacctggccgccctctgg cccttcctgg gcatcgtggc 1050 tgaggtgctg gtgctggtca ccatcatcttcatctacgag aagcgccgga 1100 agcccgagga cgtcctggat gatgacgacg ccggctctgcacccctgaag 1150 agcagcgggc agcaccagaa tgacaaaggc aagaacgtcc gccagaggaa1200 ctcttcctga ggcaggtggc ccgaggacgc tccctgctcc acgtctgcgc 1250cgccgccgga gtccactccc agtgcttgca agattccaag ttctcacctc 1300 ttaaagaaaacccaccccgt agattcccat catacacttc cttctttttt 1350 aaaaaagttg ggttttctccattcaggatt ctgttcctta ggtttttttc 1400 cttctgaagt gtttcacgag agcccgggagctgctgccct gcggccccgt 1450 ctgtggcttt cagcctctgg gtctgagtca tggccgggtgggcggcacag 1500 ccttctccac tggccggagt cagtgccagg tccttgccct ttgtggaaag1550 tcacaggtca cacgaggggc cccgtgtcct gcctgtctga agccaatgct 1600gtctggttgc gccatttttg tgcttttatg tttaatttta tgagggccac 1650 gggtctgtgttcgactcagc ctcagggacg actctgacct cttggccaca 1700 gaggactcac ttgcccacaccgagggcgac cccgtcacag cctcaagtca 1750 ctcccaagcc ccctccttgt ctgtgcatccgggggcagct ctggaggggg 1800 tttgctgggg aactggcgcc atcgccggga ctccagaaccgcagaagcct 1850 ccccagctca cccctggagg acggccggct ctctatagca ccagggctca1900 cgtgggaacc cccctcccac ccaccgccac aataaagatc gcccccacct 1950ccacccaaaa a 1961 84 385 PRT Homo Sapien 84 Met Ala Ala Ala Leu Phe ValLeu Leu Gly Phe Ala Leu Leu Gly 1 5 10 15 Thr His Gly Ala Ser Gly AlaAla Gly Phe Val Gln Ala Pro Leu 20 25 30 Ser Gln Gln Arg Trp Val Gly GlySer Val Glu Leu His Cys Glu 35 40 45 Ala Val Gly Ser Pro Val Pro Glu IleGln Trp Trp Phe Glu Gly 50 55 60 Gln Gly Pro Asn Asp Thr Cys Ser Gln LeuTrp Asp Gly Ala Arg 65 70 75 Leu Asp Arg Val His Ile His Ala Thr Tyr HisGln His Ala Ala 80 85 90 Ser Thr Ile Ser Ile Asp Thr Leu Val Glu Glu AspThr Gly Thr 95 100 105 Tyr Glu Cys Arg Ala Ser Asn Asp Pro Asp Arg AsnHis Leu Thr 110 115 120 Arg Ala Pro Arg Val Lys Trp Val Arg Ala Gln AlaVal Val Leu 125 130 135 Val Leu Glu Pro Gly Thr Val Phe Thr Thr Val GluAsp Leu Gly 140 145 150 Ser Lys Ile Leu Leu Thr Cys Ser Leu Asn Asp SerAla Thr Glu 155 160 165 Val Thr Gly His Arg Trp Leu Lys Gly Gly Val ValLeu Lys Glu 170 175 180 Asp Ala Leu Pro Gly Gln Lys Thr Glu Phe Lys ValAsp Ser Asp 185 190 195 Asp Gln Trp Gly Glu Tyr Ser Cys Val Phe Leu ProGlu Pro Met 200 205 210 Gly Thr Ala Asn Ile Gln Leu His Gly Pro Pro ArgVal Lys Ala 215 220 225 Val Lys Ser Ser Glu His Ile Asn Glu Gly Glu ThrAla Met Leu 230 235 240 Val Cys Lys Ser Glu Ser Val Pro Pro Val Thr AspTrp Ala Trp 245 250 255 Tyr Lys Ile Thr Asp Ser Glu Asp Lys Ala Leu MetAsn Gly Ser 260 265 270 Glu Ser Arg Phe Phe Val Ser Ser Ser Gln Gly ArgSer Glu Leu 275 280 285 His Ile Glu Asn Leu Asn Met Glu Ala Asp Pro GlyGln Tyr Arg 290 295 300 Cys Asn Gly Thr Ser Ser Lys Gly Ser Asp Gln AlaIle Ile Thr 305 310 315 Leu Arg Val Arg Ser His Leu Ala Ala Leu Trp ProPhe Leu Gly 320 325 330 Ile Val Ala Glu Val Leu Val Leu Val Thr Ile IlePhe Ile Tyr 335 340 345 Glu Lys Arg Arg Lys Pro Glu Asp Val Leu Asp AspAsp Asp Ala 350 355 360 Gly Ser Ala Pro Leu Lys Ser Ser Gly Gln His GlnAsn Asp Lys 365 370 375 Gly Lys Asn Val Arg Gln Arg Asn Ser Ser 380 38585 1002 DNA Homo Sapien 85 ggctcgagca aagacatacg aacagggagg aaggccgactgaaagaaaga 50 cggagaagag gagagagaag ccagggccga gcgtgccagc aggcggatgg 100agggcggcct ggtggaggag gagacgtagt ggcctgggct gagctgggtg 150 ggccgggagaagcgggtgcc tcagagtggg ggtgggggca tgggaggggc 200 aggcattctg ctgctgctgctggctggggc gggggtggtg gtggcctgga 250 gacccccaaa gggaaagtgt cccctgcgctgctcctgctc taaagacagc 300 gccctgtgtg agggctcccc ggacctgccc gtcagcttctctccgaccct 350 gctgtcactc tcactcgtca ggacgggagt cacccagctg aaggccggca400 gcttcctgag aattccgtct ctgcacctgc tcctcttcac ctccaactcc 450ttctccgtga ttgaggacga tgcatttgcg ggcctgtccc acctgcagta 500 cctcttcatcgaggacaatg agattggctc catctctaag aatgccctca 550 gaggacttcg ctcgcttacacacctaagcc tggccaataa ccatctggag 600 accctcccca gattcctgtt ccgaggcctggacaccctta ctcacgtgga 650 cctccgcggg aacccgttcc agtgtgactg ccgcgtcctctggctcctgc 700 agtggatgcc caccgtgaat gccagcgtgg ggaccggcgc ctgtgcgggc750 cccgcctccc tgagccacat gcagctccac cacctcgacc ccaagacttt 800caagtgcaga gccataggtg gggggctttc ccgatggggt gggaggcggg 850 agatctgggggaaaggctgc cagggccaag aggctcgtct cactccctgc 900 cctgccattt cccggagtgggaagaccctg agcaagcagc actgccttcc 950 tgagccccag ttttctcatc tgtaaagtgggggtaataaa cagtgatata 1000 gg 1002 86 261 PRT Homo Sapien 86 Met Gly GlyAla Gly Ile Leu Leu Leu Leu Leu Ala Gly Ala Gly 1 5 10 15 Val Val ValAla Trp Arg Pro Pro Lys Gly Lys Cys Pro Leu Arg 20 25 30 Cys Ser Cys SerLys Asp Ser Ala Leu Cys Glu Gly Ser Pro Asp 35 40 45 Leu Pro Val Ser PheSer Pro Thr Leu Leu Ser Leu Ser Leu Val 50 55 60 Arg Thr Gly Val Thr GlnLeu Lys Ala Gly Ser Phe Leu Arg Ile 65 70 75 Pro Ser Leu His Leu Leu LeuPhe Thr Ser Asn Ser Phe Ser Val 80 85 90 Ile Glu Asp Asp Ala Phe Ala GlyLeu Ser His Leu Gln Tyr Leu 95 100 105 Phe Ile Glu Asp Asn Glu Ile GlySer Ile Ser Lys Asn Ala Leu 110 115 120 Arg Gly Leu Arg Ser Leu Thr HisLeu Ser Leu Ala Asn Asn His 125 130 135 Leu Glu Thr Leu Pro Arg Phe LeuPhe Arg Gly Leu Asp Thr Leu 140 145 150 Thr His Val Asp Leu Arg Gly AsnPro Phe Gln Cys Asp Cys Arg 155 160 165 Val Leu Trp Leu Leu Gln Trp MetPro Thr Val Asn Ala Ser Val 170 175 180 Gly Thr Gly Ala Cys Ala Gly ProAla Ser Leu Ser His Met Gln 185 190 195 Leu His His Leu Asp Pro Lys ThrPhe Lys Cys Arg Ala Ile Gly 200 205 210 Gly Gly Leu Ser Arg Trp Gly GlyArg Arg Glu Ile Trp Gly Lys 215 220 225 Gly Cys Gln Gly Gln Glu Ala ArgLeu Thr Pro Cys Pro Ala Ile 230 235 240 Ser Arg Ser Gly Lys Thr Leu SerLys Gln His Cys Leu Pro Glu 245 250 255 Pro Gln Phe Ser His Leu 260 872945 DNA Homo Sapien 87 cggacgcgtg gggcggcgag agcagctgca gttcgcatctcaggcagtac 50 ctagaggagc tgccggtgcc tcctcagaac atctcctgat cgctacccag 100gaccaggcac caaggacagg gagtcccagg cgcacacccc ccattctggg 150 tcccccaggcccagaccccc actctgccac aggttgcatc ttgacctggt 200 cctcctgcag aagtggcccctgtggtcctg ctctgagact cgtccctggg 250 cgcccctgca gcccctttct atgactccatctggatttgg ctggctgtgg 300 ggacgcggtc cgaggggcgg cctggctctc agcgtggtggcagccagctc 350 tctggccacc atggcaaatg ctgagatctg aggggacaag gctctacagc400 ctcagccagg ggcactcagc tgttgcaggg tgtgatggag aacaaagcta 450tgtacctaca caccgtcagc gactgtgaca ccagctccat ctgtgaggat 500 tcctttgatggcaggagcct gtccaagctg aacctgtgtg aggatggtcc 550 atgtcacaaa cggcgggcaagcatctgctg tacccagctg gggtccctgt 600 cggccctgaa gcatgctgtc ctggggctctacctgctggt cttcctgatt 650 cttgtgggca tcttcatctt agcagggcca ccgggacccaaaggtgatca 700 gggggatgaa ggaaaggaag gcaggcctgg catccctgga ttgcctggac750 ttcgaggtct gcccggggag agaggtaccc caggattgcc cgggcccaag 800ggcgatgatg ggaagctggg ggccacagga ccaatgggca tgcgtgggtt 850 caaaggtgaccgaggcccaa aaggagagaa aggagagaaa ggagacagag 900 ctggggatgc cagtggcgtggaggccccga tgatgatccg cctggtgaat 950 ggctcaggtc cgcacgaggg ccgcgtggaagtgtaccacg accggcgctg 1000 gggcaccgtg tgtgacgacg gctgggacaa gaaggacggagacgtggtgt 1050 gccgcatgct cggcttccgc ggtgtggagg aggtgtaccg cacagctcga1100 ttcgggcaag gcactgggag gatctggatg gatgacgttg cctgcaaggg 1150cacagaggaa accatcttcc gctgcagctt ctccaaatgg ggggtgacaa 1200 actgtggacatgccgaagat gccagcgtga catgcaacag acactgaaag 1250 tgggcagagc ccaagttcggggtcctgcac agagcaccct tgctgcatcc 1300 ctggggtggg gcacagctcg gggccaccctgaccatgcct cgaccacacc 1350 ccgtccagca ttctcagtcc tcacacctgc atcccaggaccgtgggggcc 1400 ggtcgtcatt tccctcttga acatgtgctc cgaagtataa ctctgggacc1450 tactgcccgt ctctctcttc caccaggttc ctgcatgagg agccctgatc 1500aactggatca ccactttgcc cagcctctga acaccatgca ccaggcctca 1550 atatcccagttccctttggc cttttagtta caggtgaatg ctgagaatgt 1600 gtcagagaca agtgcagcagcagcgatggt tggtagtata gatcatttac 1650 tcttcagaca attcccaaac ctccattagtccaagagttt ctacatcttc 1700 ctccccagca agaggcaacg tcaagtgatg aatttcccccctttactctg 1750 cctctgctcc ccatttgcta gtttgaggaa gtgacataga ggagaagcca1800 gctgtagggg caagagggaa atgcaagtca cctgcaggaa tccagctaga 1850tttggagaag ggaatgaaac taacattgaa tgactaccat ggcacgctaa 1900 atagtatcttgggtgccaaa ttcatgtatc cacttagctg cattggtcca 1950 gggcatgtca gtctggatacagccttacct tcaggtagca cttaactggt 2000 ccattcacct agactgcaag taagaagacaaaatgactga gaccgtgtgc 2050 ccacctgaac ttattgtctt tacttggcct gagctaaaagcttgggtgca 2100 ggacctgtgt aactagaaag ttgcctactt cagaacctcc agggcgtgag2150 tgcaaggtca aacatgactg gcttccaggc cgaccatcaa tgtaggagga 2200gagctgatgt ggagggtgac atgggggctg cccatgttaa acctgagtcc 2250 agtgctctggcattgggcag tcacggttaa agccaagtca tgtgtgtctc 2300 agctgtttgg aggtgatgattttgcatctt ccaagcctct tcaggtgtga 2350 atctgtggtc aggaaaacac aagtcctaatggaaccctta ggggggaagg 2400 aaatgaagat tccctataac ctctgggggt ggggagtaggaataaggggc 2450 cttgggcctc cataaatctg caatctgcac cctcctccta gagacaggga2500 gatcgtgttc tgctttttac atgaggagca gaactgggcc atacacgtgt 2550tcaagaacta ggggagctac ctggtagcaa gtgagtgcag acccacctca 2600 ccttgggggaatctcaaact cataggcctc agatacacga tcacctgtca 2650 tatcaggtga gcactggcctgcttggggag agacctgggc ccctccaggt 2700 gtaggaacag caacactcct ggctgacaactaagccaata tggccctagg 2750 tcattcttgc ttccaatatg cttgccactc cttaaatgtcctaatgatga 2800 gaaactctct ttctgaccaa ttgctatgtt tacataacac gcatgtactc2850 atgcatccct tgccagagcc catatatgta tgcatatata aacatagcac 2900tttttactac atagctcagc acattgcaag gtttgcattt aagtt 2945 88 270 PRT HomoSapien 88 Met Glu Asn Lys Ala Met Tyr Leu His Thr Val Ser Asp Cys Asp 15 10 15 Thr Ser Ser Ile Cys Glu Asp Ser Phe Asp Gly Arg Ser Leu Ser 2025 30 Lys Leu Asn Leu Cys Glu Asp Gly Pro Cys His Lys Arg Arg Ala 35 4045 Ser Ile Cys Cys Thr Gln Leu Gly Ser Leu Ser Ala Leu Lys His 50 55 60Ala Val Leu Gly Leu Tyr Leu Leu Val Phe Leu Ile Leu Val Gly 65 70 75 IlePhe Ile Leu Ala Gly Pro Pro Gly Pro Lys Gly Asp Gln Gly 80 85 90 Asp GluGly Lys Glu Gly Arg Pro Gly Ile Pro Gly Leu Pro Gly 95 100 105 Leu ArgGly Leu Pro Gly Glu Arg Gly Thr Pro Gly Leu Pro Gly 110 115 120 Pro LysGly Asp Asp Gly Lys Leu Gly Ala Thr Gly Pro Met Gly 125 130 135 Met ArgGly Phe Lys Gly Asp Arg Gly Pro Lys Gly Glu Lys Gly 140 145 150 Glu LysGly Asp Arg Ala Gly Asp Ala Ser Gly Val Glu Ala Pro 155 160 165 Met MetIle Arg Leu Val Asn Gly Ser Gly Pro His Glu Gly Arg 170 175 180 Val GluVal Tyr His Asp Arg Arg Trp Gly Thr Val Cys Asp Asp 185 190 195 Gly TrpAsp Lys Lys Asp Gly Asp Val Val Cys Arg Met Leu Gly 200 205 210 Phe ArgGly Val Glu Glu Val Tyr Arg Thr Ala Arg Phe Gly Gln 215 220 225 Gly ThrGly Arg Ile Trp Met Asp Asp Val Ala Cys Lys Gly Thr 230 235 240 Glu GluThr Ile Phe Arg Cys Ser Phe Ser Lys Trp Gly Val Thr 245 250 255 Asn CysGly His Ala Glu Asp Ala Ser Val Thr Cys Asn Arg His 260 265 270 89 2758DNA Homo Sapien 89 gtcgccgcga gggacgcaga gagcaccctc cacgcccagatgcctgcgta 50 gtttttgtga ccagtccgct cctgcctccc cctggggcag tagaggggga 100gcgatggaga actggactgg caggccctgg ctgtatctgc tgctgcttct 150 gtccctccctcagctctgct tggatcagga ggtgttgtcc ggacactctc 200 ttcagacacc tacagaggagggccagggcc ccgaaggtgt ctggggacct 250 tgggtccagt gggcctcttg ctcccagccctgcggggtgg gggtgcagcg 300 caggagccgg acatgtcagc tccctacagt gcagctccacccgagtctgc 350 ccctccctcc ccggccccca agacatccag aagccctcct cccccggggc400 cagggtccca gaccccagac ttctccagaa accctcccct tgtacaggac 450acagtctcgg ggaaggggtg gcccacttcg aggtcccgct tcccacctag 500 ggagagaggagacccaggag attcgagcgg ccaggaggtc ccggcttcga 550 gaccccatca agccaggaatgttcggttat gggagagtgc cctttgcatt 600 gccactgcac cggaaccgca ggcaccctcggagcccaccc agatctgagc 650 tgtccctgat ctcttctaga ggggaagagg ctattccgtcccctactcca 700 agagcagagc cattctccgc aaacggcagc ccccaaactg agctccctcc750 cacagaactg tctgtccaca ccccatcccc ccaagcagaa cctctaagcc 800ctgaaactgc tcagacagag gtggccccca gaaccaggcc tgccccccta 850 cggcatcaccccagagccca ggcctctggc acagagcccc cctcacccac 900 gcactcctta ggagaaggtggcttcttccg tgcatcccct cagccacgaa 950 ggccaagttc ccagggttgg gccagtccccaggtagcagg gagacgccct 1000 gatccttttc cttcggtccc tcggggccga ggccagcagggccaagggcc 1050 ttggggaacg ggggggactc ctcacgggcc ccgcctggag cctgaccctc1100 agcacccggg cgcctggctg cccctgctga gcaacggccc ccatgccagc 1150tccctctgga gcctctttgc tcccagtagc cctattccaa gatgttctgg 1200 ggagagtgaacagctaagag cctgcagcca agcgccctgc ccccctgagc 1250 agccagaccc ccgggccctgcagtgcgcag cctttaactc ccaggaattc 1300 atgggccagc tgtatcagtg ggagcccttcactgaagtcc agggctccca 1350 gcgctgtgaa ctgaactgcc ggccccgtgg cttccgcttctatgtccgtc 1400 acactgaaaa ggtccaggat gggaccctgt gtcagcctgg agcccctgac1450 atctgtgtgg ctggacgctg tctgagcccc ggctgtgatg ggatccttgg 1500ctctggcagg cgtcctgatg gctgtggagt ctgtgggggt gatgattcta 1550 cctgtcgccttgtttcgggg aacctcactg accgaggggg ccccctgggc 1600 tatcagaaga tcttgtggattccagcggga gccttgcggc tccagattgc 1650 ccagctccgg cctagctcca actacctggcacttcgtggc cctgggggcc 1700 ggtccatcat caatgggaac tgggctgtgg atccccctgggtcctacagg 1750 gccggcggga ccgtctttcg atataaccgt cctcccaggg aggagggcaa1800 aggggagagt ctgtcggctg aaggccccac cacccagcct gtggatgtct 1850atatgatctt tcaggaggaa aacccaggcg ttttttatca gtatgtcatc 1900 tcttcacctcctccaatcct tgagaacccc accccagagc cccctgtccc 1950 ccagcttcag ccggagattctgagggtgga gcccccactt gctccggcac 2000 cccgcccagc ccggacccca ggcaccctccagcgtcaggt gcggatcccc 2050 cagatgcccg ccccgcccca tcccaggaca cccctggggtctccagctgc 2100 gtactggaaa cgagtgggac actctgcatg ctcagcgtcc tgcgggaaag2150 gtgtctggcg ccccattttc ctctgcatct cccgtgagtc gggagaggaa 2200ctggatgaac gcagctgtgc cgcgggtgcc aggcccccag cctcccctga 2250 accctgccacggcaccccat gccccccata ctgggaggct ggcgagtgga 2300 catcctgcag ccgctcctgtggccccggca cccagcaccg ccagctgcag 2350 tgccggcagg aatttggggg gggtggctcctcggtgcccc cggagcgctg 2400 tggacatctc ccccggccca acatcaccca gtcttgccagctgcgcctct 2450 gtggccattg ggaagttggc tctccttgga gccagtgctc cgtgcggtgc2500 ggccggggcc agagaagccg gcaggttcgc tgtgttggga acaacggtga 2550tgaagtgagc gagcaggagt gtgcgtcagg ccccccacag ccccccagca 2600 gagaggcctgtgacatgggg ccctgtacta ctgcctggtt ccacagcgac 2650 tggagctcca aggtgagcccggaaccccca gccatatcct gcatcctggg 2700 taaccatgcc caggacacct cagcctttccagcatagctc aataaacttg 2750 tattgatc 2758 90 877 PRT Homo Sapien 90 MetGlu Asn Trp Thr Gly Arg Pro Trp Leu Tyr Leu Leu Leu Leu 1 5 10 15 LeuSer Leu Pro Gln Leu Cys Leu Asp Gln Glu Val Leu Ser Gly 20 25 30 His SerLeu Gln Thr Pro Thr Glu Glu Gly Gln Gly Pro Glu Gly 35 40 45 Val Trp GlyPro Trp Val Gln Trp Ala Ser Cys Ser Gln Pro Cys 50 55 60 Gly Val Gly ValGln Arg Arg Ser Arg Thr Cys Gln Leu Pro Thr 65 70 75 Val Gln Leu His ProSer Leu Pro Leu Pro Pro Arg Pro Pro Arg 80 85 90 His Pro Glu Ala Leu LeuPro Arg Gly Gln Gly Pro Arg Pro Gln 95 100 105 Thr Ser Pro Glu Thr LeuPro Leu Tyr Arg Thr Gln Ser Arg Gly 110 115 120 Arg Gly Gly Pro Leu ArgGly Pro Ala Ser His Leu Gly Arg Glu 125 130 135 Glu Thr Gln Glu Ile ArgAla Ala Arg Arg Ser Arg Leu Arg Asp 140 145 150 Pro Ile Lys Pro Gly MetPhe Gly Tyr Gly Arg Val Pro Phe Ala 155 160 165 Leu Pro Leu His Arg AsnArg Arg His Pro Arg Ser Pro Pro Arg 170 175 180 Ser Glu Leu Ser Leu IleSer Ser Arg Gly Glu Glu Ala Ile Pro 185 190 195 Ser Pro Thr Pro Arg AlaGlu Pro Phe Ser Ala Asn Gly Ser Pro 200 205 210 Gln Thr Glu Leu Pro ProThr Glu Leu Ser Val His Thr Pro Ser 215 220 225 Pro Gln Ala Glu Pro LeuSer Pro Glu Thr Ala Gln Thr Glu Val 230 235 240 Ala Pro Arg Thr Arg ProAla Pro Leu Arg His His Pro Arg Ala 245 250 255 Gln Ala Ser Gly Thr GluPro Pro Ser Pro Thr His Ser Leu Gly 260 265 270 Glu Gly Gly Phe Phe ArgAla Ser Pro Gln Pro Arg Arg Pro Ser 275 280 285 Ser Gln Gly Trp Ala SerPro Gln Val Ala Gly Arg Arg Pro Asp 290 295 300 Pro Phe Pro Ser Val ProArg Gly Arg Gly Gln Gln Gly Gln Gly 305 310 315 Pro Trp Gly Thr Gly GlyThr Pro His Gly Pro Arg Leu Glu Pro 320 325 330 Asp Pro Gln His Pro GlyAla Trp Leu Pro Leu Leu Ser Asn Gly 335 340 345 Pro His Ala Ser Ser LeuTrp Ser Leu Phe Ala Pro Ser Ser Pro 350 355 360 Ile Pro Arg Cys Ser GlyGlu Ser Glu Gln Leu Arg Ala Cys Ser 365 370 375 Gln Ala Pro Cys Pro ProGlu Gln Pro Asp Pro Arg Ala Leu Gln 380 385 390 Cys Ala Ala Phe Asn SerGln Glu Phe Met Gly Gln Leu Tyr Gln 395 400 405 Trp Glu Pro Phe Thr GluVal Gln Gly Ser Gln Arg Cys Glu Leu 410 415 420 Asn Cys Arg Pro Arg GlyPhe Arg Phe Tyr Val Arg His Thr Glu 425 430 435 Lys Val Gln Asp Gly ThrLeu Cys Gln Pro Gly Ala Pro Asp Ile 440 445 450 Cys Val Ala Gly Arg CysLeu Ser Pro Gly Cys Asp Gly Ile Leu 455 460 465 Gly Ser Gly Arg Arg ProAsp Gly Cys Gly Val Cys Gly Gly Asp 470 475 480 Asp Ser Thr Cys Arg LeuVal Ser Gly Asn Leu Thr Asp Arg Gly 485 490 495 Gly Pro Leu Gly Tyr GlnLys Ile Leu Trp Ile Pro Ala Gly Ala 500 505 510 Leu Arg Leu Gln Ile AlaGln Leu Arg Pro Ser Ser Asn Tyr Leu 515 520 525 Ala Leu Arg Gly Pro GlyGly Arg Ser Ile Ile Asn Gly Asn Trp 530 535 540 Ala Val Asp Pro Pro GlySer Tyr Arg Ala Gly Gly Thr Val Phe 545 550 555 Arg Tyr Asn Arg Pro ProArg Glu Glu Gly Lys Gly Glu Ser Leu 560 565 570 Ser Ala Glu Gly Pro ThrThr Gln Pro Val Asp Val Tyr Met Ile 575 580 585 Phe Gln Glu Glu Asn ProGly Val Phe Tyr Gln Tyr Val Ile Ser 590 595 600 Ser Pro Pro Pro Ile LeuGlu Asn Pro Thr Pro Glu Pro Pro Val 605 610 615 Pro Gln Leu Gln Pro GluIle Leu Arg Val Glu Pro Pro Leu Ala 620 625 630 Pro Ala Pro Arg Pro AlaArg Thr Pro Gly Thr Leu Gln Arg Gln 635 640 645 Val Arg Ile Pro Gln MetPro Ala Pro Pro His Pro Arg Thr Pro 650 655 660 Leu Gly Ser Pro Ala AlaTyr Trp Lys Arg Val Gly His Ser Ala 665 670 675 Cys Ser Ala Ser Cys GlyLys Gly Val Trp Arg Pro Ile Phe Leu 680 685 690 Cys Ile Ser Arg Glu SerGly Glu Glu Leu Asp Glu Arg Ser Cys 695 700 705 Ala Ala Gly Ala Arg ProPro Ala Ser Pro Glu Pro Cys His Gly 710 715 720 Thr Pro Cys Pro Pro TyrTrp Glu Ala Gly Glu Trp Thr Ser Cys 725 730 735 Ser Arg Ser Cys Gly ProGly Thr Gln His Arg Gln Leu Gln Cys 740 745 750 Arg Gln Glu Phe Gly GlyGly Gly Ser Ser Val Pro Pro Glu Arg 755 760 765 Cys Gly His Leu Pro ArgPro Asn Ile Thr Gln Ser Cys Gln Leu 770 775 780 Arg Leu Cys Gly His TrpGlu Val Gly Ser Pro Trp Ser Gln Cys 785 790 795 Ser Val Arg Cys Gly ArgGly Gln Arg Ser Arg Gln Val Arg Cys 800 805 810 Val Gly Asn Asn Gly AspGlu Val Ser Glu Gln Glu Cys Ala Ser 815 820 825 Gly Pro Pro Gln Pro ProSer Arg Glu Ala Cys Asp Met Gly Pro 830 835 840 Cys Thr Thr Ala Trp PheHis Ser Asp Trp Ser Ser Lys Val Ser 845 850 855 Pro Glu Pro Pro Ala IleSer Cys Ile Leu Gly Asn His Ala Gln 860 865 870 Asp Thr Ser Ala Phe ProAla 875 91 2597 DNA Homo Sapien 91 cgagtatttt cccaccatct ccagccggaaactgaccaag aactctgagg 50 cggatggcat gttcgcgtac gtcttccatg atgagttcgtggcctcgatg 100 attaagatcc cttcggacac cttcaccatc atccctgact ttgatatcta150 ctatgtctat ggttttagca gtggcaactt tgtctacttt ttgaccctcc 200aacctgagat ggtgtctcca ccaggctcca ccaccaagga gcaggtgtat 250 acatccaagctcgtgaggct ttgcaaggag gacacagcct tcaactccta 300 tgtagaggtg cccattggctgtgagcgcag tggggtggag taccgcctgc 350 tgcaggctgc ctacctgtcc aaagcgggggccgtgcttgg caggaccctt 400 ggagtccatc cagatgatga cctgctcttc accgtcttctccaagggcca 450 gaagcggaaa atgaaatccc tggatgagtc ggccctgtgc atcttcatct500 tgaagcagat aaatgaccgc attaaggagc ggctgcagtc ttgttaccgg 550ggcgagggca cgctggacct ggcctggctc aaggtgaagg acatcccctg 600 cagcagtgcgctcttaacca ttgacgataa cttctgtggc ctggacatga 650 atgctcccct gggagtgtccgacatggtgc gtggaattcc cgtcttcacg 700 gaggacaggg accgcatgac gtctgtcatcgcatatgtct acaagaacca 750 ctctctggcc tttgtgggca ccaaaagtgg caagctgaagaaggtgcctg 800 gtaccagcct ctgccctacc cttgagctac agacgggacc ccgatcccac850 agagcaacag tgactctgga actcctgttc tccagctgtt catcaaactg 900agaaaaactt cagagctgtg taggcttatt tagtgtgttg tcagccttgg 950 atattggaaaatggaaacag atgagacaca tctacctccc tgtgacccca 1000 gccatacatc atagctcatgtcctgccacc ccaagtcctt agggaaaaaa 1050 gactttggag aatgtgtctc tgcttagcttggctaggtag ttggtctctt 1100 ttctctgccc caagcgtccc ctgggtaatt ttggacaatggagtgtaggc 1150 atgtttgact cttgtggtgt tatcacttgt atatgtcagt gaaactaact1200 gattctccca tcggaatata gttatctctt gggcctgata tatggtagga 1250taaccttatg ctcatctgtc cacttctgca gccaagtcgc ctggccagtg 1300 tgtgtgtgtgtgtgtgtgtg tgtgtgtgtg tgtgtgtatg cttatctgtg 1350 tttaaaggtg tgtgtgcatacacagggcag agaggatgga gcccaccgta 1400 ctgcagcatc atgtaattaa ctcagtgctcagaaccatcc cagcctctgc 1450 gggaaagaga aaagtaagcc aacagtgcct gatgagctgatcatatgtgc 1500 aaaagctctg ttggcatctg gtccaggaga gcacccaaaa aaagttaatt1550 ggtgttgtcc agtctccttt ccttaagact atggttacaa caaagcgtga 1600gcagtgtctc ctgcatggcc actatccagc acaattccat aattccccca 1650 tagagccggtggggaggagg aggtgagtgg cgaaggaagt ggaaacactt 1700 ggtgtcatgt gctcctatcatttctactag cttactggga aataaagtgt 1750 agtcaagagt gtatgaaggc aagatgtaaaattagcgact ggtgctaatc 1800 tggttacttg aaaacaagtg aaagtgctgt agatttgttctgttgctaag 1850 aaccaccaca ctaaacctcg tatagttcct ggaggatata caacagtgta1900 attctcttta gggtgtgcca caggttcctg gcctgtggga gggaatgaat 1950caggagggct cttgagaacc ttcatctgtg tgcttgcact gaaagtgagt 2000 cccaaagctggagatttagt gagagcaggc aacccctctg tgtctcactg 2050 tccatattct ggaggcagaggtttgtaaca ggccatgtgc acctgcatag 2100 ggatgggtaa agcaaggact ttgaaagagttgaaaagcat tataaacagt 2150 tgttcagaaa tacgtcccag gagttccatg tgaaactggctctgtgtgca 2200 ttgaagcatg gctgttggga attctaactg gtccaacact cctgcaaaac2250 aatgtgtaaa tatttaggaa gaaacttgaa aatagtcaaa tcctttgaac 2300tggtgacaat tttttaaaga atcaattcta atttgtttca agggtaataa 2350 tcaccaagatacacatttca gcatttattt agtctatcaa aaattggaat 2400 tgatatatac actcatttataggagaatgg ttaggtagat ttggtatatt 2450 tatgtagtca ttgaaaactt agtttataaaggccaatctt gtaactgatt 2500 cttgtgtgat aacattcagt gaaaaagcat gagacaattagaaagcatga 2550 tacaatgaat aaaataaaaa ctggaaagag aaccatcaaa atgctaa 259792 280 PRT Homo Sapien 92 Met Phe Ala Tyr Val Phe His Asp Glu Phe ValAla Ser Met Ile 1 5 10 15 Lys Ile Pro Ser Asp Thr Phe Thr Ile Ile ProAsp Phe Asp Ile 20 25 30 Tyr Tyr Val Tyr Gly Phe Ser Ser Gly Asn Phe ValTyr Phe Leu 35 40 45 Thr Leu Gln Pro Glu Met Val Ser Pro Pro Gly Ser ThrThr Lys 50 55 60 Glu Gln Val Tyr Thr Ser Lys Leu Val Arg Leu Cys Lys GluAsp 65 70 75 Thr Ala Phe Asn Ser Tyr Val Glu Val Pro Ile Gly Cys Glu Arg80 85 90 Ser Gly Val Glu Tyr Arg Leu Leu Gln Ala Ala Tyr Leu Ser Lys 95100 105 Ala Gly Ala Val Leu Gly Arg Thr Leu Gly Val His Pro Asp Asp 110115 120 Asp Leu Leu Phe Thr Val Phe Ser Lys Gly Gln Lys Arg Lys Met 125130 135 Lys Ser Leu Asp Glu Ser Ala Leu Cys Ile Phe Ile Leu Lys Gln 140145 150 Ile Asn Asp Arg Ile Lys Glu Arg Leu Gln Ser Cys Tyr Arg Gly 155160 165 Glu Gly Thr Leu Asp Leu Ala Trp Leu Lys Val Lys Asp Ile Pro 170175 180 Cys Ser Ser Ala Leu Leu Thr Ile Asp Asp Asn Phe Cys Gly Leu 185190 195 Asp Met Asn Ala Pro Leu Gly Val Ser Asp Met Val Arg Gly Ile 200205 210 Pro Val Phe Thr Glu Asp Arg Asp Arg Met Thr Ser Val Ile Ala 215220 225 Tyr Val Tyr Lys Asn His Ser Leu Ala Phe Val Gly Thr Lys Ser 230235 240 Gly Lys Leu Lys Lys Val Pro Gly Thr Ser Leu Cys Pro Thr Leu 245250 255 Glu Leu Gln Thr Gly Pro Arg Ser His Arg Ala Thr Val Thr Leu 260265 270 Glu Leu Leu Phe Ser Ser Cys Ser Ser Asn 275 280 93 2883 DNA HomoSapien 93 ccttatcaga caaaggacga gatggaaaat acaagataat ttacagtgga 50gaagaattag aatgtaacct gaaagatctt agaccagcaa cagattatca 100 tgtgagggtgtatgccatgt acaattccgt aaagggatcc tgctccgagc 150 ctgttagctt caccacccacagctgtgcac ccgagtgtcc tttcccccct 200 aagctggcac ataggagcaa aagttcactaaccctgcagt ggaaggcacc 250 aattgacaac ggttcaaaaa tcaccaacta ccttttagagtgggatgagg 300 gaaaaagaaa tagtggtttc agacagtgct tcttcgggag ccagaagcac350 tgcaagttga caaagctttg tccggcaatg gggtacacat tcaggctggc 400cgctcgaaac gacattggca ccagtggtta tagccaagag gtggtgtgct 450 acacattaggaaatatccct cagatgcctt ctgcactaag gctggttcga 500 gctggcatca catgggtcacgttgcagtgg agtaagccag aaggctgttc 550 acccgaggaa gtgatcacct acaccttggaaattcaggag gatgaaaatg 600 ataacctttt ccacccaaaa tacactggag aggatttaacctgtactgtg 650 aaaaatctca aaagaagcac acagtataaa ttcaggctga ctgcttctaa700 tacggaagga aaaagctgtc caagcgaagt tcttgtttgt acgacgagtc 750ctgacaggcc tggacctcct accagaccgc ttgtcaaagg cccagttaca 800 tctcatggctttagtgtcaa atgggatccc cctaaggaca atggtggttc 850 agaaatcctc aagtacttgctagagattac tgatggaaat tctgaagcga 900 atcagtggga agtggcctac agtgggtcggctaccgaata caccttcacc 950 cacttgaaac caggcacttt gtacaaactc cgagcatgctgcatcagtac 1000 cggcggacac agccagtgtt ctgaaagtct ccctgttcgc acactaagca1050 ttgcaccagg tcaatgtcga ccaccgaggg ttttgggtag accaaagcac 1100aaagaagtcc acttagagtg ggatgttcct gcatcggaaa gtggctgtga 1150 ggtctcagagtacagcgtgg agatgacgga gcccgaagac gtagcctcgg 1200 aagtgtacca tggcccagagctggagtgca ccgtcggcaa cctgcttcct 1250 ggaaccgtgt atcgcttccg ggtgagggctctgaatgatg gagggtatgg 1300 tccctattct gatgtctcag aaattaccac tgctgcagggcctcctggac 1350 aatgcaaagc accttgtatt tcttgtacac ctgatggatg tgtcttagtg1400 ggttgggaga gtcctgatag ttctggtgct gacatctcag agtacaggtt 1450ggaatgggga gaagatgaag aatccttaga actcatttat catgggacag 1500 acacccgttttgaaataaga gacctgttgc ctgctgcaca gtattgctgt 1550 agactacagg ccttcaatcaagcaggggca gggccgtaca gtgaacttgt 1600 cctttgccag acgccagcgt ctgcccctgaccccgtctcc actctctgtg 1650 tcctggagga ggagcccctt gatgcctacc ctgattcaccttctgcgtgc 1700 cttgtactga actgggaaga gccgtgcaat aacggatctg aaatccttgc1750 ttacaccatt gatctaggag acactagcat taccgtgggc aacaccacca 1800tgcatgttat gaaagatctc cttccagaaa ccacctaccg gatcagaatt 1850 caggctataaatgaaattgg agctggacca tttagtcagt tcattaaagc 1900 aaaaactcgg ccattaccacccttgcctcc taggctagaa tgtgctgctg 1950 ctggtcctca gagcctgaag ctaaaatggggagacagtaa ctccaagaca 2000 catgctgctg aggacattgt gtacacacta cagctggaggacagaaacaa 2050 gaggtttatt tcaatctaca gaggacccag ccacacctac aaggtccaga2100 gactgacgga attcacatgc tactccttca gaatccaggc agcaagcgag 2150gctggagaag ggcccttctc agaaacctat accttcagca caaccaaaag 2200 tgtcccccccaccatcaaag cacctcgagt aacacagtta gaagtaaatt 2250 catgtgaaat tttatgggagacggtaccat caatgaaagg tgaccctgtt 2300 aactacattc tgcaggtatt ggttggaagagaatctgagt acaaacaggt 2350 gtacaaggga gaagaagcca cattccaaat ctcaggcctccagaccaaca 2400 cagactacag gttccgcgta tgtgcgtgtc gtcgctgttt agacacctct2450 caggagctaa gcggagcctt cagcccctct gcggcttttg tattacaacg 2500aagtgaggtc atgcttacag gggacatggg gagcttagat gatcccaaaa 2550 tgaagagcatgatgcctact gatgaacagt ttgcagccat cattgtgctt 2600 ggctttgcaa ctttgtccattttatttgcc tttatattac agtacttctt 2650 aatgaagtaa acccaacaaa actagaggtatgaattaatg ctacacattt 2700 taatacacac atttattcag atactcccct ttttaaagcccttttgtttt 2750 ttgatttata tactctgttt tacagattta gctagaaaaa aaatgtcagt2800 gttttggtgc acctttttga aatgcaaaac taggaaaagg ttaaactgga 2850ttttttttta aaaaaaaaaa aaaaaaaaaa aaa 2883 94 847 PRT Homo Sapien 94 MetTyr Asn Ser Val Lys Gly Ser Cys Ser Glu Pro Val Ser Phe 1 5 10 15 ThrThr His Ser Cys Ala Pro Glu Cys Pro Phe Pro Pro Lys Leu 20 25 30 Ala HisArg Ser Lys Ser Ser Leu Thr Leu Gln Trp Lys Ala Pro 35 40 45 Ile Asp AsnGly Ser Lys Ile Thr Asn Tyr Leu Leu Glu Trp Asp 50 55 60 Glu Gly Lys ArgAsn Ser Gly Phe Arg Gln Cys Phe Phe Gly Ser 65 70 75 Gln Lys His Cys LysLeu Thr Lys Leu Cys Pro Ala Met Gly Tyr 80 85 90 Thr Phe Arg Leu Ala AlaArg Asn Asp Ile Gly Thr Ser Gly Tyr 95 100 105 Ser Gln Glu Val Val CysTyr Thr Leu Gly Asn Ile Pro Gln Met 110 115 120 Pro Ser Ala Leu Arg LeuVal Arg Ala Gly Ile Thr Trp Val Thr 125 130 135 Leu Gln Trp Ser Lys ProGlu Gly Cys Ser Pro Glu Glu Val Ile 140 145 150 Thr Tyr Thr Leu Glu IleGln Glu Asp Glu Asn Asp Asn Leu Phe 155 160 165 His Pro Lys Tyr Thr GlyGlu Asp Leu Thr Cys Thr Val Lys Asn 170 175 180 Leu Lys Arg Ser Thr GlnTyr Lys Phe Arg Leu Thr Ala Ser Asn 185 190 195 Thr Glu Gly Lys Ser CysPro Ser Glu Val Leu Val Cys Thr Thr 200 205 210 Ser Pro Asp Arg Pro GlyPro Pro Thr Arg Pro Leu Val Lys Gly 215 220 225 Pro Val Thr Ser His GlyPhe Ser Val Lys Trp Asp Pro Pro Lys 230 235 240 Asp Asn Gly Gly Ser GluIle Leu Lys Tyr Leu Leu Glu Ile Thr 245 250 255 Asp Gly Asn Ser Glu AlaAsn Gln Trp Glu Val Ala Tyr Ser Gly 260 265 270 Ser Ala Thr Glu Tyr ThrPhe Thr His Leu Lys Pro Gly Thr Leu 275 280 285 Tyr Lys Leu Arg Ala CysCys Ile Ser Thr Gly Gly His Ser Gln 290 295 300 Cys Ser Glu Ser Leu ProVal Arg Thr Leu Ser Ile Ala Pro Gly 305 310 315 Gln Cys Arg Pro Pro ArgVal Leu Gly Arg Pro Lys His Lys Glu 320 325 330 Val His Leu Glu Trp AspVal Pro Ala Ser Glu Ser Gly Cys Glu 335 340 345 Val Ser Glu Tyr Ser ValGlu Met Thr Glu Pro Glu Asp Val Ala 350 355 360 Ser Glu Val Tyr His GlyPro Glu Leu Glu Cys Thr Val Gly Asn 365 370 375 Leu Leu Pro Gly Thr ValTyr Arg Phe Arg Val Arg Ala Leu Asn 380 385 390 Asp Gly Gly Tyr Gly ProTyr Ser Asp Val Ser Glu Ile Thr Thr 395 400 405 Ala Ala Gly Pro Pro GlyGln Cys Lys Ala Pro Cys Ile Ser Cys 410 415 420 Thr Pro Asp Gly Cys ValLeu Val Gly Trp Glu Ser Pro Asp Ser 425 430 435 Ser Gly Ala Asp Ile SerGlu Tyr Arg Leu Glu Trp Gly Glu Asp 440 445 450 Glu Glu Ser Leu Glu LeuIle Tyr His Gly Thr Asp Thr Arg Phe 455 460 465 Glu Ile Arg Asp Leu LeuPro Ala Ala Gln Tyr Cys Cys Arg Leu 470 475 480 Gln Ala Phe Asn Gln AlaGly Ala Gly Pro Tyr Ser Glu Leu Val 485 490 495 Leu Cys Gln Thr Pro AlaSer Ala Pro Asp Pro Val Ser Thr Leu 500 505 510 Cys Val Leu Glu Glu GluPro Leu Asp Ala Tyr Pro Asp Ser Pro 515 520 525 Ser Ala Cys Leu Val LeuAsn Trp Glu Glu Pro Cys Asn Asn Gly 530 535 540 Ser Glu Ile Leu Ala TyrThr Ile Asp Leu Gly Asp Thr Ser Ile 545 550 555 Thr Val Gly Asn Thr ThrMet His Val Met Lys Asp Leu Leu Pro 560 565 570 Glu Thr Thr Tyr Arg IleArg Ile Gln Ala Ile Asn Glu Ile Gly 575 580 585 Ala Gly Pro Phe Ser GlnPhe Ile Lys Ala Lys Thr Arg Pro Leu 590 595 600 Pro Pro Leu Pro Pro ArgLeu Glu Cys Ala Ala Ala Gly Pro Gln 605 610 615 Ser Leu Lys Leu Lys TrpGly Asp Ser Asn Ser Lys Thr His Ala 620 625 630 Ala Glu Asp Ile Val TyrThr Leu Gln Leu Glu Asp Arg Asn Lys 635 640 645 Arg Phe Ile Ser Ile TyrArg Gly Pro Ser His Thr Tyr Lys Val 650 655 660 Gln Arg Leu Thr Glu PheThr Cys Tyr Ser Phe Arg Ile Gln Ala 665 670 675 Ala Ser Glu Ala Gly GluGly Pro Phe Ser Glu Thr Tyr Thr Phe 680 685 690 Ser Thr Thr Lys Ser ValPro Pro Thr Ile Lys Ala Pro Arg Val 695 700 705 Thr Gln Leu Glu Val AsnSer Cys Glu Ile Leu Trp Glu Thr Val 710 715 720 Pro Ser Met Lys Gly AspPro Val Asn Tyr Ile Leu Gln Val Leu 725 730 735 Val Gly Arg Glu Ser GluTyr Lys Gln Val Tyr Lys Gly Glu Glu 740 745 750 Ala Thr Phe Gln Ile SerGly Leu Gln Thr Asn Thr Asp Tyr Arg 755 760 765 Phe Arg Val Cys Ala CysArg Arg Cys Leu Asp Thr Ser Gln Glu 770 775 780 Leu Ser Gly Ala Phe SerPro Ser Ala Ala Phe Val Leu Gln Arg 785 790 795 Ser Glu Val Met Leu ThrGly Asp Met Gly Ser Leu Asp Asp Pro 800 805 810 Lys Met Lys Ser Met MetPro Thr Asp Glu Gln Phe Ala Ala Ile 815 820 825 Ile Val Leu Gly Phe AlaThr Leu Ser Ile Leu Phe Ala Phe Ile 830 835 840 Leu Gln Tyr Phe Leu MetLys 845 95 4725 DNA Homo Sapien 95 caattcggcc tcgctccttg tgattgcgctaaaccttccg tcctcagctg 50 agaacgctcc accacctccc cggatcgctc atctcttggctgccctccca 100 ctgttcctga tgttatttta ctccccgtat cccctactcg ttcttcacaa150 ttctgtaggt gagtggttcc agctggtgcc tggcctgtgt ctcttggatg 200ccctgtggct tcagtccgtc tcctgttgcc caccacctcg tccctgggcc 250 gcctgataccccagcccaac agctaaggtg tggatggaca gtagggggct 300 ggcttctctc actggtcaggggtcttctcc cctgtctgcc tcccggagct 350 aggactgcag aggggcctat catggtgcttgcaggccccc tggctgtctc 400 gctgttgctg cccagcctca cactgctggt gtcccacctctccagctccc 450 aggatgtctc cagtgagccc agcagtgagc agcagctgtg cgcccttagc500 aagcacccca ccgtggcctt tgaagacctg cagccgtggg tctctaactt 550cacctaccct ggagcccggg atttctccca gctggctttg gacccctccg 600 ggaaccagctcatcgtggga gccaggaact acctcttcag actcagcctt 650 gccaatgtct ctcttcttcaggccacagag tgggcctcca gtgaggacac 700 gcgccgctcc tgccaaagca aagggaagactgaggaggag tgtcagaact 750 acgtgcgagt cctgatcgtc gccggccgga aggtgttcatgtgtggaacc 800 aatgcctttt cccccatgtg caccagcaga caggtgggga acctcagccg850 gactattgag aagatcaatg gtgtggcccg ctgcccctat gacccacgcc 900acaactccac agctgtcatc tcctcccagg gggagctcta tgcagccacg 950 gtcatcgacttctcaggtcg ggaccctgcc atctaccgca gcctgggcag 1000 tgggccaccg cttcgcactgcccaatataa ctccaagtgg cttaatgagc 1050 caaacttcgt ggcagcctat gatattgggctgtttgcata cttcttcctg 1100 cgggagaacg cagtggagca cgactgtgga cgcaccgtgtactctcgcgt 1150 ggcccgcgtg tgcaagaatg acgtgggggg ccgattcctg ctggaggaca1200 catggaccac attcatgaag gcccggctca actgctcccg cccgggcgag 1250gtccccttct actataacga gctgcagagt gccttccact tgccggagca 1300 ggacctcatctatggagttt tcacaaccaa cgtaaacagc atcgcggctt 1350 ctgctgtctg cgccttcaacctcagtgcta tctcccaggc tttcaatggc 1400 ccatttcgct accaggagaa ccccagggctgcctggctcc ccatagccaa 1450 ccccatcccc aatttccagt gtggcaccct gcctgagaccggtcccaacg 1500 agaacctgac ggagcgcagc ctgcaggacg cgcagcgcct cttcctgatg1550 agcgaggccg tgcagccggt gacacccgag ccctgtgtca cccaggacag 1600cgtgcgcttc tcacacctcg tggtggacct ggtgcaggct aaagacacgc 1650 tctaccatgtactctacatt ggcaccgagt cgggcaccat cctgaaggcg 1700 ctgtccacgg cgagccgcagcctccacggc tgctacctgg aggagctgca 1750 cgtgctgccc cccgggcgcc gcgagcccctgcgcagcctg cgcatcctgc 1800 acagcgcccg cgcgctcttc gtggggctga gagacggcgtcctgcgggtc 1850 ccactggaga ggtgcgccgc ctaccgcagc cagggggcat gcctgggggc1900 ccgggacccg tactgtggct gggacgggaa gcagcaacgt tgcagcacac 1950tcgaggacag ctccaacatg agcctctgga cccagaacat caccgcctgt 2000 cctgtgcggaatgtgacacg ggatgggggc ttcggcccat ggtcaccatg 2050 gcaaccatgt gagcacttggatggggacaa ctcaggctct tgcctgtgtc 2100 gagctcgatc ctgtgattcc cctcgaccccgctgtggggg ccttgactgc 2150 ctggggccag ccatccacat cgccaactgc tccaggaatggggcgtggac 2200 cccgtggtca tcgtgggcgc tgtgcagcac gtcctgtggc atcggcttcc2250 aggtccgcca gcgaagttgc agcaaccctg ctccccgcca cgggggccgc 2300atcttcgtgg gcaagagccg ggaggaacgg ttctgtaatg agaacacgcc 2350 ttgcccggtgcccatcttct gggcttcctg gggctcctgg agcaagtgca 2400 gcagcaactg tggagggggcatgcagtcgc ggcgtcgggc ctgcgagaac 2450 ggcaactcct gcctgggctg cggcgagttcaagacgtgca accccgaggg 2500 ctgccccgaa gtgcggcgca acaccccctg gacgccgtggctgcccgtga 2550 acgtgacgca gggcggggca cggcaggagc agcggttccg cttcacctgc2600 cgcgcgcccc ttgcagaccc gcacggcctg cagttcggca ggagaaggac 2650cgagacgagg acctgtcccg cggacggctc cggctcctgc gacaccgacg 2700 ccctggtggaggtcctcctg cgcagcggga gcacctcccc gcacacggtg 2750 agcgggggct gggccgcctggggcccgtgg tcgtcctgct cccgggactg 2800 cgagctgggc ttccgcgtcc gcaagagaacgtgcactaac ccggagcccc 2850 gcaacggggg cctgccctgc gtgggcgatg ctgccgagtaccaggactgc 2900 aacccccagg cttgcccagt tcggggtgct tggtcctgct ggacctcatg2950 gtctccatgc tcagcttcct gtggtggggg tcactatcaa cgcacccgtt 3000cctgcaccag ccccgcaccc tccccaggtg aggacatctg tctcgggctg 3050 cacacggaggaggcactatg tgccacacag gcctgcccag gctggtcgcc 3100 ctggtctgag tggagtaagtgcactgacga cggagcccag agccgaagcc 3150 ggcactgtga ggagctcctc ccagggtccagcgcctgtgc tggaaacagc 3200 agccagagcc gcccctgccc ctacagcgag attcccgtcatcctgccagc 3250 ctccagcatg gaggaggcca ccgactgtgc aggtaaaaga aaccggacct3300 acctcatgct gcggtcctcc cagccctcca gcaccccact ccaaagtctg 3350gactctttcc acatcctgct ccagacagcc aagctttgtt ggggtcccca 3400 ctgctttgagatgggttcaa tctcatccac ttggtggcca cgggcatctc 3450 ctgcttcttg ggctctgggctcctgaccct agcagtgtac ctgtcttgcc 3500 agcactgcca gcgtcagtcc caggagtccacactggtcca tcctgccacc 3550 cccaaccatt tgcactacaa gggcggaggc accccgaagaatgaaaagta 3600 cacacccatg gaattcaaga ccctgaacaa gaataacttg atccctgatg3650 acagagccaa cttctaccca ttgcagcaga ccaatgtgta cacgactact 3700tactacccaa gccccctgaa caaacacagc ttccggcccg aggcctcacc 3750 tggacaacggtgcttcccca acagctgata ccgccgtcct ggggacttgg 3800 gcttcttgcc ttcataaggcacagagcaga tggagatggg acagtggagc 3850 cagtttggtt ttctccctct gcactaggccaagaacttgc tgccttgcct 3900 gtggggggtc ccatccggct tcagagagct ctggctggcattgaccatgg 3950 gggaaagggc tggtttcagg ctgacatatg gccgcaggtc cagttcagcc4000 caggtctctc atggttatct tccaacccac tgtcacgctg acactatgct 4050gccatgcctg ggctgtggac ctactgggca tttgaggaat tggagaatgg 4100 agatggcaagagggcaggct tttaagtttg ggttggagac aacttcctgt 4150 ggcccccaca agctgagtctggccttctcc agctggcccc aaaaaaggcc 4200 tttgctacat cctgattatc tctgaaagtaatcaatcaag tggctccagt 4250 agctctggat tttctgccag ggctgggcca ttgtggtgctgccccagtat 4300 gacatgggac caaggccagc gcaggttatc cacctctgcc tggaagtcta4350 tactctaccc agggcatccc tctggtcaga ggcagtgagt actgggaact 4400ggaggctgac ctgtgcttag aagtccttta atctgggctg gtacaggcct 4450 cagccttgccctcaatgcac gaaaggtggc ccaggagaga ggatcaatgc 4500 cataggaggc agaagtctggcctctgtgcc tctatggaga ctatcttcca 4550 gttgctgctc aacagagttg ttggctgagacctgcttggg agtctctgct 4600 ggcccttcat ctgttcagga acacacacac acacacactcacacacgcac 4650 acacaatcac aatttgctac agcaacaaaa aagacattgg gctgtggcat4700 tattaattaa agatgatatc cagtc 4725 96 1092 PRT Homo Sapien 96 Met ProCys Gly Phe Ser Pro Ser Pro Val Ala His His Leu Val 1 5 10 15 Pro GlyPro Pro Asp Thr Pro Ala Gln Gln Leu Arg Cys Gly Trp 20 25 30 Thr Val GlyGly Trp Leu Leu Ser Leu Val Arg Gly Leu Leu Pro 35 40 45 Cys Leu Pro ProGly Ala Arg Thr Ala Glu Gly Pro Ile Met Val 50 55 60 Leu Ala Gly Pro LeuAla Val Ser Leu Leu Leu Pro Ser Leu Thr 65 70 75 Leu Leu Val Ser His LeuSer Ser Ser Gln Asp Val Ser Ser Glu 80 85 90 Pro Ser Ser Glu Gln Gln LeuCys Ala Leu Ser Lys His Pro Thr 95 100 105 Val Ala Phe Glu Asp Leu GlnPro Trp Val Ser Asn Phe Thr Tyr 110 115 120 Pro Gly Ala Arg Asp Phe SerGln Leu Ala Leu Asp Pro Ser Gly 125 130 135 Asn Gln Leu Ile Val Gly AlaArg Asn Tyr Leu Phe Arg Leu Ser 140 145 150 Leu Ala Asn Val Ser Leu LeuGln Ala Thr Glu Trp Ala Ser Ser 155 160 165 Glu Asp Thr Arg Arg Ser CysGln Ser Lys Gly Lys Thr Glu Glu 170 175 180 Glu Cys Gln Asn Tyr Val ArgVal Leu Ile Val Ala Gly Arg Lys 185 190 195 Val Phe Met Cys Gly Thr AsnAla Phe Ser Pro Met Cys Thr Ser 200 205 210 Arg Gln Val Gly Asn Leu SerArg Thr Ile Glu Lys Ile Asn Gly 215 220 225 Val Ala Arg Cys Pro Tyr AspPro Arg His Asn Ser Thr Ala Val 230 235 240 Ile Ser Ser Gln Gly Glu LeuTyr Ala Ala Thr Val Ile Asp Phe 245 250 255 Ser Gly Arg Asp Pro Ala IleTyr Arg Ser Leu Gly Ser Gly Pro 260 265 270 Pro Leu Arg Thr Ala Gln TyrAsn Ser Lys Trp Leu Asn Glu Pro 275 280 285 Asn Phe Val Ala Ala Tyr AspIle Gly Leu Phe Ala Tyr Phe Phe 290 295 300 Leu Arg Glu Asn Ala Val GluHis Asp Cys Gly Arg Thr Val Tyr 305 310 315 Ser Arg Val Ala Arg Val CysLys Asn Asp Val Gly Gly Arg Phe 320 325 330 Leu Leu Glu Asp Thr Trp ThrThr Phe Met Lys Ala Arg Leu Asn 335 340 345 Cys Ser Arg Pro Gly Glu ValPro Phe Tyr Tyr Asn Glu Leu Gln 350 355 360 Ser Ala Phe His Leu Pro GluGln Asp Leu Ile Tyr Gly Val Phe 365 370 375 Thr Thr Asn Val Asn Ser IleAla Ala Ser Ala Val Cys Ala Phe 380 385 390 Asn Leu Ser Ala Ile Ser GlnAla Phe Asn Gly Pro Phe Arg Tyr 395 400 405 Gln Glu Asn Pro Arg Ala AlaTrp Leu Pro Ile Ala Asn Pro Ile 410 415 420 Pro Asn Phe Gln Cys Gly ThrLeu Pro Glu Thr Gly Pro Asn Glu 425 430 435 Asn Leu Thr Glu Arg Ser LeuGln Asp Ala Gln Arg Leu Phe Leu 440 445 450 Met Ser Glu Ala Val Gln ProVal Thr Pro Glu Pro Cys Val Thr 455 460 465 Gln Asp Ser Val Arg Phe SerHis Leu Val Val Asp Leu Val Gln 470 475 480 Ala Lys Asp Thr Leu Tyr HisVal Leu Tyr Ile Gly Thr Glu Ser 485 490 495 Gly Thr Ile Leu Lys Ala LeuSer Thr Ala Ser Arg Ser Leu His 500 505 510 Gly Cys Tyr Leu Glu Glu LeuHis Val Leu Pro Pro Gly Arg Arg 515 520 525 Glu Pro Leu Arg Ser Leu ArgIle Leu His Ser Ala Arg Ala Leu 530 535 540 Phe Val Gly Leu Arg Asp GlyVal Leu Arg Val Pro Leu Glu Arg 545 550 555 Cys Ala Ala Tyr Arg Ser GlnGly Ala Cys Leu Gly Ala Arg Asp 560 565 570 Pro Tyr Cys Gly Trp Asp GlyLys Gln Gln Arg Cys Ser Thr Leu 575 580 585 Glu Asp Ser Ser Asn Met SerLeu Trp Thr Gln Asn Ile Thr Ala 590 595 600 Cys Pro Val Arg Asn Val ThrArg Asp Gly Gly Phe Gly Pro Trp 605 610 615 Ser Pro Trp Gln Pro Cys GluHis Leu Asp Gly Asp Asn Ser Gly 620 625 630 Ser Cys Leu Cys Arg Ala ArgSer Cys Asp Ser Pro Arg Pro Arg 635 640 645 Cys Gly Gly Leu Asp Cys LeuGly Pro Ala Ile His Ile Ala Asn 650 655 660 Cys Ser Arg Asn Gly Ala TrpThr Pro Trp Ser Ser Trp Ala Leu 665 670 675 Cys Ser Thr Ser Cys Gly IleGly Phe Gln Val Arg Gln Arg Ser 680 685 690 Cys Ser Asn Pro Ala Pro ArgHis Gly Gly Arg Ile Phe Val Gly 695 700 705 Lys Ser Arg Glu Glu Arg PheCys Asn Glu Asn Thr Pro Cys Pro 710 715 720 Val Pro Ile Phe Trp Ala SerTrp Gly Ser Trp Ser Lys Cys Ser 725 730 735 Ser Asn Cys Gly Gly Gly MetGln Ser Arg Arg Arg Ala Cys Glu 740 745 750 Asn Gly Asn Ser Cys Leu GlyCys Gly Glu Phe Lys Thr Cys Asn 755 760 765 Pro Glu Gly Cys Pro Glu ValArg Arg Asn Thr Pro Trp Thr Pro 770 775 780 Trp Leu Pro Val Asn Val ThrGln Gly Gly Ala Arg Gln Glu Gln 785 790 795 Arg Phe Arg Phe Thr Cys ArgAla Pro Leu Ala Asp Pro His Gly 800 805 810 Leu Gln Phe Gly Arg Arg ArgThr Glu Thr Arg Thr Cys Pro Ala 815 820 825 Asp Gly Ser Gly Ser Cys AspThr Asp Ala Leu Val Glu Val Leu 830 835 840 Leu Arg Ser Gly Ser Thr SerPro His Thr Val Ser Gly Gly Trp 845 850 855 Ala Ala Trp Gly Pro Trp SerSer Cys Ser Arg Asp Cys Glu Leu 860 865 870 Gly Phe Arg Val Arg Lys ArgThr Cys Thr Asn Pro Glu Pro Arg 875 880 885 Asn Gly Gly Leu Pro Cys ValGly Asp Ala Ala Glu Tyr Gln Asp 890 895 900 Cys Asn Pro Gln Ala Cys ProVal Arg Gly Ala Trp Ser Cys Trp 905 910 915 Thr Ser Trp Ser Pro Cys SerAla Ser Cys Gly Gly Gly His Tyr 920 925 930 Gln Arg Thr Arg Ser Cys ThrSer Pro Ala Pro Ser Pro Gly Glu 935 940 945 Asp Ile Cys Leu Gly Leu HisThr Glu Glu Ala Leu Cys Ala Thr 950 955 960 Gln Ala Cys Pro Gly Trp SerPro Trp Ser Glu Trp Ser Lys Cys 965 970 975 Thr Asp Asp Gly Ala Gln SerArg Ser Arg His Cys Glu Glu Leu 980 985 990 Leu Pro Gly Ser Ser Ala CysAla Gly Asn Ser Ser Gln Ser Arg 995 1000 1005 Pro Cys Pro Tyr Ser GluIle Pro Val Ile Leu Pro Ala Ser Ser 1010 1015 1020 Met Glu Glu Ala ThrAsp Cys Ala Gly Lys Arg Asn Arg Thr Tyr 1025 1030 1035 Leu Met Leu ArgSer Ser Gln Pro Ser Ser Thr Pro Leu Gln Ser 1040 1045 1050 Leu Asp SerPhe His Ile Leu Leu Gln Thr Ala Lys Leu Cys Trp 1055 1060 1065 Gly ProHis Cys Phe Glu Met Gly Ser Ile Ser Ser Thr Trp Trp 1070 1075 1080 ProArg Ala Ser Pro Ala Ser Trp Ala Leu Gly Ser 1085 1090 97 3391 DNA HomoSapien 97 caagccctcc cagcatcccc tctcctgtgt tcctccccag ttctctactc 50agagttgact gaccagagat ttatcagctt ggagggctgg aggtgtggat 100 ccatggggtagcctcaacgc atctgcccct ccaccccagc cagctcatgg 150 gccacgtggc ctggcccagcctcagcaccc agggccagtg aacagagccc 200 tggctggagt ccaaacatgt ggggcctggtgaggctcctg ctggcctggc 250 tgggtggctg gggctgcatg gggcgtctgg cagccccagcccgggcctgg 300 gcagggtccc gggaacaccc agggcctgct ctgctgcgga ctcgaaggag350 ctgggtctgg aaccagttct ttgtcattga ggaatatgct ggtccagagc 400ctgttctcat tggcaagctg cactcggatg ttgaccgggg agagggccgc 450 accaagtacctgttgaccgg ggagggggca ggcaccgtat ttgtgattga 500 tgaggccaca ggcaatattcatgttaccaa gagccttgac cgggaggaaa 550 aggcgcaata tgtgctactg gcccaagccgtggaccgagc ctccaaccgg 600 cccctggagc ccccatcaga gttcatcatc aaagtgcaagacatcaacga 650 caatccaccc atttttcccc ttgggcccta ccatgccacc gtgcccgaga700 tgtccaatgt cgggacatca gtgatccagg tgactgctca cgatgctgat 750gaccccagct atgggaacag tgccaagctg gtgtacactg ttctggatgg 800 actgcctttcttctctgtgg acccccagac tggagtggtg cgtacagcca 850 tccccaacat ggaccgggagacacaggagg agttcttggt ggtgatccag 900 gccaaggaca tgggcggcca catgggggggctgtcaggca gcactacggt 950 gactgtcacg ctcagcgatg tcaacgacaa cccccccaagttcccacaga 1000 gcctatacca gttctccgtg gtggagacag ctggacctgg cacactggtg1050 ggccggctcc gggcccagga cccagacctg ggggacaacg ccctgatggc 1100atacagcatc ctggatgggg aggggtctga ggccttcagc atcagcacag 1150 acttgcagggtcgagacggg ctcctcactg tccgcaagcc cctagacttt 1200 gagagccagc gctcctactccttccgtgtc gaggccacca acacgctcat 1250 tgacccagcc tatctgcggc gagggcccttcaaggatgtg gcctctgtgc 1300 gtgtggcagt gcaagatgcc ccagagccac ctgccttcacccaggctgcc 1350 taccacctga cagtgcctga gaacaaggcc ccggggaccc tggtaggcca1400 gatctccgcg gctgacctgg actcccctgc cagcccaatc agatactcca 1450tcctccccca ctcagatccg gagcgttgct tctctatcca gcccgaggaa 1500 ggcaccatccatacagcagc acccctggat cgcgaggctc gcgcctggca 1550 caacctcact gtgctggctacagagctcga cagttctgca caggcctcgc 1600 gcgtgcaagt ggccatccag accctggatgagaatgacaa tgctccccag 1650 ctggctgagc cctacgatac ttttgtgtgt gactctgcagctcctggcca 1700 gctgattcag gtcatccggg ccctggacag agatgaagtt ggcaacagta1750 gccatgtctc ctttcaaggt cctctgggcc ctgatgccaa ctttactgtc 1800caggacaacc gagatggctc cgccagcctg ctgctgccct cccgccctgc 1850 tccaccccgccatgccccct acttggttcc catagaactg tgggactggg 1900 ggcagccggc gctgagcagcactgccacag tgactgttag tgtgtgccgc 1950 tgccagcctg acggctctgt ggcatcctgctggcctgagg ctcacctctc 2000 agctgctggg ctcagcaccg gcgccctgct tgccatcatcacctgtgtgg 2050 gtgccctgct tgccctggtg gtgctcttcg tggccctgcg gcggcagaag2100 caagaagcac tgatggtact ggaggaggag gacgtccgag agaacatcat 2150cacctacgac gacgagggcg gcggcgagga ggacaccgag gccttcgaca 2200 tcacggccttgcagaacccg gacggggcgg cccccccggc gcccggccct 2250 cccgcgcgcc gagacgtgttgccccgggcc cgggtgtcgc gccagcccag 2300 accccccggc cccgccgacg tggcgcagctcctggcgctg cggctccgcg 2350 aggcggacga ggaccccggc gtacccccgt acgactcggtgcaggtgtac 2400 ggctacgagg gccgcggctc ctcttgcggc tccctcagct ccctgggctc2450 cggcagcgaa gccggcggcg cccccggccc cgcggagccg ctggacgact 2500ggggtccgct cttccgcacc ctggccgagc tgtatggggc caaggagccc 2550 ccggccccctgagcgcccgg gctggcccgg cccaccgcgg ggggggggca 2600 gcgggcacag gccctctgagtgagccccac ggggtccagg cgggcggcag 2650 cagcccaggg gccccaggcc tcctccctgtccttgtgtcc ctccttgctt 2700 ccccggggca ccctcgctct cacctccctc ctcctgagtcggtgtgtgtg 2750 tctctctcca ggaatctttg tctctatctg tgacacgctc ctctgtccgg2800 gcctgggttt cctgccctgg ccctggccct gcgatctctc actgtgattc 2850ctctccttcc tccgtggcgt tttgtctctg cagttctgaa gctcacacat 2900 agtctccctgcgtcttcctt gcccatacac atgctctgtg tctgtctcct 2950 gcccacatct cccttccttctctctgggtc cctgtgactg gctttttgtt 3000 tttttctgtt gtccatccca aaatcaagagaaacttccag ccactgctgc 3050 ccaccctcct gcaggggatg ttgtgcccca gacctgcctgcatggttcca 3100 tccattactc atggcctcag cctcatcctg gctccactgg cctccagctg3150 agagagggaa ccagcctgcc tcccagggca agagctccag cctcccgtgt 3200ggccgcctcc ctggagctct gcccagctgc cagcttcccc tgggcatccc 3250 agccctgggcattgtcttgt gtgcttcctg agggagtagg gaaaggaaag 3300 ggggaggcgg ctggggaaggggaaagaggg aggaagggga ggggcctcca 3350 tctctaattt cataataaac aaacactttattttgtaaaa c 3391 98 781 PRT Homo Sapien 98 Met Trp Gly Leu Val Arg LeuLeu Leu Ala Trp Leu Gly Gly Trp 1 5 10 15 Gly Cys Met Gly Arg Leu AlaAla Pro Ala Arg Ala Trp Ala Gly 20 25 30 Ser Arg Glu His Pro Gly Pro AlaLeu Leu Arg Thr Arg Arg Ser 35 40 45 Trp Val Trp Asn Gln Phe Phe Val IleGlu Glu Tyr Ala Gly Pro 50 55 60 Glu Pro Val Leu Ile Gly Lys Leu His SerAsp Val Asp Arg Gly 65 70 75 Glu Gly Arg Thr Lys Tyr Leu Leu Thr Gly GluGly Ala Gly Thr 80 85 90 Val Phe Val Ile Asp Glu Ala Thr Gly Asn Ile HisVal Thr Lys 95 100 105 Ser Leu Asp Arg Glu Glu Lys Ala Gln Tyr Val LeuLeu Ala Gln 110 115 120 Ala Val Asp Arg Ala Ser Asn Arg Pro Leu Glu ProPro Ser Glu 125 130 135 Phe Ile Ile Lys Val Gln Asp Ile Asn Asp Asn ProPro Ile Phe 140 145 150 Pro Leu Gly Pro Tyr His Ala Thr Val Pro Glu MetSer Asn Val 155 160 165 Gly Thr Ser Val Ile Gln Val Thr Ala His Asp AlaAsp Asp Pro 170 175 180 Ser Tyr Gly Asn Ser Ala Lys Leu Val Tyr Thr ValLeu Asp Gly 185 190 195 Leu Pro Phe Phe Ser Val Asp Pro Gln Thr Gly ValVal Arg Thr 200 205 210 Ala Ile Pro Asn Met Asp Arg Glu Thr Gln Glu GluPhe Leu Val 215 220 225 Val Ile Gln Ala Lys Asp Met Gly Gly His Met GlyGly Leu Ser 230 235 240 Gly Ser Thr Thr Val Thr Val Thr Leu Ser Asp ValAsn Asp Asn 245 250 255 Pro Pro Lys Phe Pro Gln Ser Leu Tyr Gln Phe SerVal Val Glu 260 265 270 Thr Ala Gly Pro Gly Thr Leu Val Gly Arg Leu ArgAla Gln Asp 275 280 285 Pro Asp Leu Gly Asp Asn Ala Leu Met Ala Tyr SerIle Leu Asp 290 295 300 Gly Glu Gly Ser Glu Ala Phe Ser Ile Ser Thr AspLeu Gln Gly 305 310 315 Arg Asp Gly Leu Leu Thr Val Arg Lys Pro Leu AspPhe Glu Ser 320 325 330 Gln Arg Ser Tyr Ser Phe Arg Val Glu Ala Thr AsnThr Leu Ile 335 340 345 Asp Pro Ala Tyr Leu Arg Arg Gly Pro Phe Lys AspVal Ala Ser 350 355 360 Val Arg Val Ala Val Gln Asp Ala Pro Glu Pro ProAla Phe Thr 365 370 375 Gln Ala Ala Tyr His Leu Thr Val Pro Glu Asn LysAla Pro Gly 380 385 390 Thr Leu Val Gly Gln Ile Ser Ala Ala Asp Leu AspSer Pro Ala 395 400 405 Ser Pro Ile Arg Tyr Ser Ile Leu Pro His Ser AspPro Glu Arg 410 415 420 Cys Phe Ser Ile Gln Pro Glu Glu Gly Thr Ile HisThr Ala Ala 425 430 435 Pro Leu Asp Arg Glu Ala Arg Ala Trp His Asn LeuThr Val Leu 440 445 450 Ala Thr Glu Leu Asp Ser Ser Ala Gln Ala Ser ArgVal Gln Val 455 460 465 Ala Ile Gln Thr Leu Asp Glu Asn Asp Asn Ala ProGln Leu Ala 470 475 480 Glu Pro Tyr Asp Thr Phe Val Cys Asp Ser Ala AlaPro Gly Gln 485 490 495 Leu Ile Gln Val Ile Arg Ala Leu Asp Arg Asp GluVal Gly Asn 500 505 510 Ser Ser His Val Ser Phe Gln Gly Pro Leu Gly ProAsp Ala Asn 515 520 525 Phe Thr Val Gln Asp Asn Arg Asp Gly Ser Ala SerLeu Leu Leu 530 535 540 Pro Ser Arg Pro Ala Pro Pro Arg His Ala Pro TyrLeu Val Pro 545 550 555 Ile Glu Leu Trp Asp Trp Gly Gln Pro Ala Leu SerSer Thr Ala 560 565 570 Thr Val Thr Val Ser Val Cys Arg Cys Gln Pro AspGly Ser Val 575 580 585 Ala Ser Cys Trp Pro Glu Ala His Leu Ser Ala AlaGly Leu Ser 590 595 600 Thr Gly Ala Leu Leu Ala Ile Ile Thr Cys Val GlyAla Leu Leu 605 610 615 Ala Leu Val Val Leu Phe Val Ala Leu Arg Arg GlnLys Gln Glu 620 625 630 Ala Leu Met Val Leu Glu Glu Glu Asp Val Arg GluAsn Ile Ile 635 640 645 Thr Tyr Asp Asp Glu Gly Gly Gly Glu Glu Asp ThrGlu Ala Phe 650 655 660 Asp Ile Thr Ala Leu Gln Asn Pro Asp Gly Ala AlaPro Pro Ala 665 670 675 Pro Gly Pro Pro Ala Arg Arg Asp Val Leu Pro ArgAla Arg Val 680 685 690 Ser Arg Gln Pro Arg Pro Pro Gly Pro Ala Asp ValAla Gln Leu 695 700 705 Leu Ala Leu Arg Leu Arg Glu Ala Asp Glu Asp ProGly Val Pro 710 715 720 Pro Tyr Asp Ser Val Gln Val Tyr Gly Tyr Glu GlyArg Gly Ser 725 730 735 Ser Cys Gly Ser Leu Ser Ser Leu Gly Ser Gly SerGlu Ala Gly 740 745 750 Gly Ala Pro Gly Pro Ala Glu Pro Leu Asp Asp TrpGly Pro Leu 755 760 765 Phe Arg Thr Leu Ala Glu Leu Tyr Gly Ala Lys GluPro Pro Ala 770 775 780 Pro 99 2855 DNA Homo Sapien 99 gccaacactggccaaacata tggggctgga atctcaacat cggtcactgg 50 gacctcaata tttggagccggaaccccaca atttggaaca cagaccccaa 100 tatttggagc agaaccccaa gatttgacatctaaaacctc aagcctggag 150 ctgaactctg aattctgggc ctgggacctt gaaatctgggactggatttc 200 cagtactgta ccctggaacc cactcttggg gacctgaacc ctgggattca250 ggcctcaaat tccaagatct ggactgtggg attccaaggg gcctgaaccc 300gagtttgggc ctgaagtcct tgctgcagac ctgagtgctt aaatctgggg 350 cttgagacctcccaatcttg actcagcacc ccaatatctg aatgcagaac 400 cccgggatcg gatctcagactctaaacccc accgtttggc tgcttagcat 450 cccaagactg gacctgggag accctgaccctgaacaaccc aaactggacc 500 cgtaaaactg gaccctagag gcccaatatt taggggtctggaaccccgag 550 tattaaggtc tggagactcc gttgccacag atttgagccg agtcaggaca600 cagtccctct acagaagcct tggggacagg aaaagcatga ccagatgctc 650cctccagagc cctgacctct gactcccctg gagctaggac tctgctccct 700 ggggctgcttctagctcagg acacccctgc ccgcgatggc catcctcccg 750 ttgctcctgt gcctgctgccgctggcccct gcctcatccc caccccagtc 800 agccacaccc agcccatgtc cccgccgctgccgctgccag acacagtcgc 850 tgcccctaag cgtgctgtgc ccaggggcag gcctcctgttcgtgccaccc 900 tcgctggacc gccgggcagc cgagctgcgg ctggcagaca acttcatcgc950 ctccgtgcgc cgccgcgacc tggccaacat gacaggcctg ctgcatctga 1000gcctgtcgcg gaacaccatc cgccacgtgg ctgccggcgc cttcgccgac 1050 ctgcgggccctgcgtgccct gcacctggat ggcaaccggc tgacctcact 1100 gggcgagggc cagctgcgcggcctggtcaa cttgcgccac ctcatcctca 1150 gcaacaacca gctggcagcg ctggcggccggcgccctgga tgattgtgcc 1200 gagacactgg aggacctcga cctctcctac aacaacctcgagcagctgcc 1250 ctgggaggcc ctgggccgcc tgggcaacgt caacacgttg ggcctcgacc1300 acaacctgct ggcttctgtg cccggcgctt tttcccgcct gcacaagctg 1350gcccggctgg acatgacctc caaccgcctg accacaatcc cacccgaccc 1400 actcttctcccgcctgcccc tgctcgccag gccccggggc tcgcccgcct 1450 ctgccctggt gctggcctttggcgggaacc ccctgcactg caactgcgag 1500 ctggtgtggc tgcgtcgcct ggcgcgggaggacgacctcg aggcctgcgc 1550 gtccccacct gctctgggcg gccgctactt ctgggcggtgggcgaggagg 1600 agtttgtctg cgagccgccc gtggtgactc accgctcacc acctctggct1650 gtgcccgcag gtcggccggc tgccctgcgc tgccgggcag tgggggaccc 1700agagccccgt gtgcgttggg tgtcacccca gggccggctg ctaggcaact 1750 caagccgtgcccgcgccttc cccaatggga cgctggagct gctggtcacc 1800 gagccgggtg atggtggcatcttcacctgc attgcggcca atgcagctgg 1850 cgaggccaca gctgctgtgg agctgactgtgggtccccca ccacctcctc 1900 agctagccaa cagcaccagc tgtgaccccc cgcgggacggggatcctgat 1950 gctctcaccc caccctccgc tgcctctgct tctgccaagg tggccgacac2000 tgggccccct accgaccgtg gcgtccaggt gactgagcac ggggccacag 2050ctgctcttgt ccagtggccg gatcagcggc ctatcccggg catccgcatg 2100 taccagatccagtacaacag ctcggctgat gacatcctcg tctacaggat 2150 gatcccggcg gagagccgctcgttcctgct gacggacctg gcgtcaggcc 2200 ggacctacga tctgtgcgtg ctcgccgtgtatgaggacag cgccacgggg 2250 ctcacggcca cgcggcctgt gggctgcgcc cgcttctccaccgaacctgc 2300 gctgcggcca tgcggggcgc cgcacgctcc cttcctgggc ggcacgatga2350 tcatcgcgct gggcggcgtc atcgtagcct cggtactggt cttcatcttc 2400gtgctgctaa tgcgctacaa ggtgcacggc ggccagcccc ccggcaaggc 2450 caagattcccgcgcctgtta gcagcgtttg ctcccagacc aacggcgccc 2500 tgggccccac gcccacgcccgccccgcccg ccccggagcc cgcggcgctc 2550 agggcccaca ccgtggtcca gctggactgcgagccctggg ggcccggcca 2600 cgaacctgtg ggaccctagc caggcgcccc cccctctaagggtcctctgg 2650 ccccacggac agcaggaccc ggacaccctg tgggacctgg cctcaaactc2700 accaaatcgc tcatggtttt taaaactctg atggggaggg tgtcggggac 2750accggggcaa aacaagaaag tcctattttt ccaaaaaaaa aaaaaaaaaa 2800 aaaaaaaaaaaaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2850 aaaaa 2855 100 627 PRTHomo Sapien 100 Met Ala Ile Leu Pro Leu Leu Leu Cys Leu Leu Pro Leu AlaPro 1 5 10 15 Ala Ser Ser Pro Pro Gln Ser Ala Thr Pro Ser Pro Cys ProArg 20 25 30 Arg Cys Arg Cys Gln Thr Gln Ser Leu Pro Leu Ser Val Leu Cys35 40 45 Pro Gly Ala Gly Leu Leu Phe Val Pro Pro Ser Leu Asp Arg Arg 5055 60 Ala Ala Glu Leu Arg Leu Ala Asp Asn Phe Ile Ala Ser Val Arg 65 7075 Arg Arg Asp Leu Ala Asn Met Thr Gly Leu Leu His Leu Ser Leu 80 85 90Ser Arg Asn Thr Ile Arg His Val Ala Ala Gly Ala Phe Ala Asp 95 100 105Leu Arg Ala Leu Arg Ala Leu His Leu Asp Gly Asn Arg Leu Thr 110 115 120Ser Leu Gly Glu Gly Gln Leu Arg Gly Leu Val Asn Leu Arg His 125 130 135Leu Ile Leu Ser Asn Asn Gln Leu Ala Ala Leu Ala Ala Gly Ala 140 145 150Leu Asp Asp Cys Ala Glu Thr Leu Glu Asp Leu Asp Leu Ser Tyr 155 160 165Asn Asn Leu Glu Gln Leu Pro Trp Glu Ala Leu Gly Arg Leu Gly 170 175 180Asn Val Asn Thr Leu Gly Leu Asp His Asn Leu Leu Ala Ser Val 185 190 195Pro Gly Ala Phe Ser Arg Leu His Lys Leu Ala Arg Leu Asp Met 200 205 210Thr Ser Asn Arg Leu Thr Thr Ile Pro Pro Asp Pro Leu Phe Ser 215 220 225Arg Leu Pro Leu Leu Ala Arg Pro Arg Gly Ser Pro Ala Ser Ala 230 235 240Leu Val Leu Ala Phe Gly Gly Asn Pro Leu His Cys Asn Cys Glu 245 250 255Leu Val Trp Leu Arg Arg Leu Ala Arg Glu Asp Asp Leu Glu Ala 260 265 270Cys Ala Ser Pro Pro Ala Leu Gly Gly Arg Tyr Phe Trp Ala Val 275 280 285Gly Glu Glu Glu Phe Val Cys Glu Pro Pro Val Val Thr His Arg 290 295 300Ser Pro Pro Leu Ala Val Pro Ala Gly Arg Pro Ala Ala Leu Arg 305 310 315Cys Arg Ala Val Gly Asp Pro Glu Pro Arg Val Arg Trp Val Ser 320 325 330Pro Gln Gly Arg Leu Leu Gly Asn Ser Ser Arg Ala Arg Ala Phe 335 340 345Pro Asn Gly Thr Leu Glu Leu Leu Val Thr Glu Pro Gly Asp Gly 350 355 360Gly Ile Phe Thr Cys Ile Ala Ala Asn Ala Ala Gly Glu Ala Thr 365 370 375Ala Ala Val Glu Leu Thr Val Gly Pro Pro Pro Pro Pro Gln Leu 380 385 390Ala Asn Ser Thr Ser Cys Asp Pro Pro Arg Asp Gly Asp Pro Asp 395 400 405Ala Leu Thr Pro Pro Ser Ala Ala Ser Ala Ser Ala Lys Val Ala 410 415 420Asp Thr Gly Pro Pro Thr Asp Arg Gly Val Gln Val Thr Glu His 425 430 435Gly Ala Thr Ala Ala Leu Val Gln Trp Pro Asp Gln Arg Pro Ile 440 445 450Pro Gly Ile Arg Met Tyr Gln Ile Gln Tyr Asn Ser Ser Ala Asp 455 460 465Asp Ile Leu Val Tyr Arg Met Ile Pro Ala Glu Ser Arg Ser Phe 470 475 480Leu Leu Thr Asp Leu Ala Ser Gly Arg Thr Tyr Asp Leu Cys Val 485 490 495Leu Ala Val Tyr Glu Asp Ser Ala Thr Gly Leu Thr Ala Thr Arg 500 505 510Pro Val Gly Cys Ala Arg Phe Ser Thr Glu Pro Ala Leu Arg Pro 515 520 525Cys Gly Ala Pro His Ala Pro Phe Leu Gly Gly Thr Met Ile Ile 530 535 540Ala Leu Gly Gly Val Ile Val Ala Ser Val Leu Val Phe Ile Phe 545 550 555Val Leu Leu Met Arg Tyr Lys Val His Gly Gly Gln Pro Pro Gly 560 565 570Lys Ala Lys Ile Pro Ala Pro Val Ser Ser Val Cys Ser Gln Thr 575 580 585Asn Gly Ala Leu Gly Pro Thr Pro Thr Pro Ala Pro Pro Ala Pro 590 595 600Glu Pro Ala Ala Leu Arg Ala His Thr Val Val Gln Leu Asp Cys 605 610 615Glu Pro Trp Gly Pro Gly His Glu Pro Val Gly Pro 620 625 101 1111 DNAHomo Sapien 101 cgactccata accgtggcct tggccccagt ccccctgact tccggacttc50 agaccagata ctgcccatat ccccttatga agtcttggcc aggcaacccc 100 tagggtgtacgttttctaaa gattaaagag gcggtgctaa gctgcagacg 150 gacttgcgac tcagccactggtgtaagtca ggcgggaggt ggcgcccaat 200 aagctcaaga gaggaggcgg gttctggaaaaaggccaata gcctgtgaag 250 gcgagtctag cagcaaccaa tagctatgag cgagaggcgggactctgagg 300 gaagtcaatc gctgccgcag gtaccgccaa tggcttttgg cgggggcgtt350 ccccaaccct gccctctctc atgaccccgc tccgggatta tggccgggac 400tgggctgctg gcgctgcgga cgctgccagg gcccagctgg gtgcgaggct 450 cgggcccttccgtgctgagc cgcctgcagg acgcggccgt ggtgcggcct 500 ggcttcctga gcacggcagaggaggagacg ctgagccgag aactggagcc 550 cgagctgcgc cgccgccgct acgaatacgatcactgggac gcggccatcc 600 acggcttccg agagacagag aagtcgcgct ggtcagaagccagccgggcc 650 atcctgcagc gcgtgcaggc ggccgccttt ggccccggcc agaccctgct700 ctcctccgtg cacgtgctgg acctggaagc ccgcggctac atcaagcccc 750acgtggacag catcaagttc tgcggggcca ccatcgccgg cctgtctctc 800 ctgtctcccagcgttatgcg gctggtgcac acccaggagc cgggggagtg 850 gctggaactc ttgctggagccgggctccct ctacatcctt aggggctcag 900 cccgttatga cttctcccat gagatccttcgggatgaaga gtccttcttt 950 ggggaacgcc ggattccccg gggccggcgc atctccgtgatctgccgctc 1000 cctccctgag ggcatggggc caggggagtc tggacagccg cccccagcct1050 gctgaccccc agctttctac agacaccaga tttgtgaata aagttgggga 1100atggacagcc t 1111 102 221 PRT Homo Sapien 102 Met Ala Gly Thr Gly LeuLeu Ala Leu Arg Thr Leu Pro Gly Pro 1 5 10 15 Ser Trp Val Arg Gly SerGly Pro Ser Val Leu Ser Arg Leu Gln 20 25 30 Asp Ala Ala Val Val Arg ProGly Phe Leu Ser Thr Ala Glu Glu 35 40 45 Glu Thr Leu Ser Arg Glu Leu GluPro Glu Leu Arg Arg Arg Arg 50 55 60 Tyr Glu Tyr Asp His Trp Asp Ala AlaIle His Gly Phe Arg Glu 65 70 75 Thr Glu Lys Ser Arg Trp Ser Glu Ala SerArg Ala Ile Leu Gln 80 85 90 Arg Val Gln Ala Ala Ala Phe Gly Pro Gly GlnThr Leu Leu Ser 95 100 105 Ser Val His Val Leu Asp Leu Glu Ala Arg GlyTyr Ile Lys Pro 110 115 120 His Val Asp Ser Ile Lys Phe Cys Gly Ala ThrIle Ala Gly Leu 125 130 135 Ser Leu Leu Ser Pro Ser Val Met Arg Leu ValHis Thr Gln Glu 140 145 150 Pro Gly Glu Trp Leu Glu Leu Leu Leu Glu ProGly Ser Leu Tyr 155 160 165 Ile Leu Arg Gly Ser Ala Arg Tyr Asp Phe SerHis Glu Ile Leu 170 175 180 Arg Asp Glu Glu Ser Phe Phe Gly Glu Arg ArgIle Pro Arg Gly 185 190 195 Arg Arg Ile Ser Val Ile Cys Arg Ser Leu ProGlu Gly Met Gly 200 205 210 Pro Gly Glu Ser Gly Gln Pro Pro Pro Ala Cys215 220 103 3583 DNA Homo Sapien 103 ctccccggcg ccgcaggcag cgtcctcctccgaagcagct gcacctgcaa 50 ctgggcagcc tggaccctcg tgccctgttc ccgggacctcgcgcaggggg 100 cgccccggga caccccctgc gggccgggtg gaggaggaag aggaggagga150 ggaagaagac gtggacaagg acccccatcc tacccagaac acctgcctgc 200gctgccgcca cttctcttta agggagagga aaagagagcc taggagaacc 250 atggggggctgcgaagtccg ggaatttctt ttgcaatttg gtttcttctt 300 gcctctgctg acagcgtggccaggcgactg cagtcacgtc tccaacaacc 350 aagttgtgtt gcttgataca acaactgtactgggagagct aggatggaaa 400 acatatccat taaatgggtg ggatgccatc actgaaatggatgaacataa 450 taggcccatt cacacatacc aggtatgtaa tgtaatggaa ccaaaccaaa500 acaactggct tcgtacaaac tggatctccc gtgatgcagc tcagaaaatt 550tatgtggaaa tgaaattcac actaagggat tgtaacagca tcccatgggt 600 cttggggacttgcaaagaaa catttaatct gttttatatg gaatcagatg 650 agtcccacgg aattaaattcaagccaaacc agtatacaaa gatcgacaca 700 attgctgctg atgagagttt tacccagatggatttgggtg atcgcatcct 750 caaactcaac actgaaattc gtgaggtggg gcctatagaaaggaaaggat 800 tttatctggc ttttcaagac attggggcgt gcattgccct ggtttcagtc850 cgtgttttct acaagaaatg ccccttcact gttcgtaact tggccatgtt 900tcctgatacc attccaaggg ttgattcctc ctctttggtt gaagtacggg 950 gttcttgtgtgaagagtgct gaagagcgtg acactcctaa actgtattgt 1000 ggagctgatg gagattggctggttcctctt ggaaggtgca tctgcagtac 1050 aggatatgaa gaaattgagg gttcttgccatgcttgcaga ccaggattct 1100 ataaagcttt tgctgggaac acaaaatgtt ctaaatgtcctccacacagt 1150 ttaacataca tggaagcaac ttctgtctgt cagtgtgaaa agggttattt1200 ccgagctgaa aaagacccac cttctatggc atgtaccagg ccaccttcag 1250ctcctaggaa tgtggttttt aacatcaatg aaacagccct tattttggaa 1300 tggagcccaccaagtgacac aggagggaga aaagatctca catacagtgt 1350 aatctgtaag aaatgtggcttagacaccag ccagtgtgag gactgtggtg 1400 gaggactccg cttcatccca agacatacaggcctgatcaa caattccgtg 1450 atagtacttg actttgtgtc tcacgtgaat tacacctttgaaatagaagc 1500 aatgaatgga gtttctgagt tgagtttttc tcccaagcca ttcacagcta1550 ttacagtgac cacggatcaa gatgcacctt ccctgatagg tgtggtaagg 1600aaggactggg catcccaaaa tagcattgcc ctatcatggc aagcacctgc 1650 tttttccaatggagccattc tggactacga gatcaagtac tatgagaaag 1700 aacatgagca gctgacctactcttccacaa ggtccaaagc ccccagtgtc 1750 atcatcacag gtcttaagcc agccaccaaatatgtatttc acatccgagt 1800 gagaactgcg acaggataca gtggctacag tcagaaatttgaatttgaaa 1850 caggagatga aacttctgac atggcagcag aacaaggaca gattctcgtg1900 atagccaccg ccgctgttgg cggattcact ctcctcgtca tcctcacttt 1950attcttcttg atcactggga gatgtcagtg gtacataaaa gccaagatga 2000 agtcagaagagaagagaaga aaccacttac agaatgggca tttgcgcttc 2050 ccgggaatta aaacttacattgatccagat acatatgaag acccatccct 2100 agcagtccat gaatttgcaa aggagattgatccctcaaga attcgtattg 2150 agagagtcat tggggcaggt gaatttggag aagtctgtagtgggcgtttg 2200 aagacaccag ggaaaagaga gatcccagtt gccattaaaa ctttgaaagg2250 tggccacatg gatcggcaaa gaagagattt tctaagagaa gctagtatca 2300tgggccagtt tgaccatcca aacatcattc gcctagaagg ggttgtcacc 2350 aaaagatccttcccggccat tggggtggag gcgttttgcc ccagcttcct 2400 gagggcaggg tttttaaatagcatccaggc cccgcatcca gtgccagggg 2450 gaggatcttt gccccccagg attcctgctggcagaccagt aatgattgtg 2500 gtggaatata tggagaatgg atccctagac tcctttttgcggaagcatga 2550 tggccacttc acagtcatcc agttggtcgg aatgctccga ggcattgcat2600 caggcatgaa gtatctttct gatatgggtt atgttcatcg agacctagcg 2650gctcggaata tactggtcaa tagcaactta gtatgcaaag tttctgattt 2700 tggtctctccagagtgctgg aagatgatcc agaagctgct tatacaacaa 2750 ctggtggaaa aatccccataaggtggacag ccccagaagc catcgcctac 2800 agaaaattct cctcagcaag cgatgcatggagctatggca ttgtcatgtg 2850 ggaggtcatg tcctatggag agagacctta ttgggaaatgtctaaccaag 2900 atgtcattct gtccattgaa gaagggtaca gacttccagc tcccatgggc2950 tgtccagcat ctctacacca gctgatgctc cactgctggc agaaggagag 3000aaatcacaga ccaaaattta ctgacattgt cagcttcctt gacaaactga 3050 tccgaaatcccagtgccctt cacaccctgg tggaggacat ccttgtaatg 3100 ccagagtccc ctggtgaagttccggaatat cctttgtttg tcacagttgg 3150 tgactggcta gattctataa agatggggcaatacaagaat aacttcgtgg 3200 cagcagggtt tacaacattt gacctgattt caagaatgagcattgatgac 3250 attagaagaa ttggagtcat acttattgga caccagagac gaatagtcag3300 cagcatacag actttacgtt tacacatgat gcacatacag gagaagggat 3350ttcatgtatg aaagtaccac aagcacctgt gttttgtgcc tcagcatttc 3400 taaaatgaacgatatcctct ctactactct ctcttctgat tctccaaaca 3450 tcacttcaca aactgcagtcttctgttcag actataggca cacaccttat 3500 gtttatgctt ccaaccagga ttttaaaatcatgctacata aatccgttct 3550 gaataacctg caactaaaaa aaaaaaaaaa aaa 3583 1041036 PRT Homo Sapien 104 Met Gly Gly Cys Glu Val Arg Glu Phe Leu Leu GlnPhe Gly Phe 1 5 10 15 Phe Leu Pro Leu Leu Thr Ala Trp Pro Gly Asp CysSer His Val 20 25 30 Ser Asn Asn Gln Val Val Leu Leu Asp Thr Thr Thr ValLeu Gly 35 40 45 Glu Leu Gly Trp Lys Thr Tyr Pro Leu Asn Gly Trp Asp AlaIle 50 55 60 Thr Glu Met Asp Glu His Asn Arg Pro Ile His Thr Tyr Gln Val65 70 75 Cys Asn Val Met Glu Pro Asn Gln Asn Asn Trp Leu Arg Thr Asn 8085 90 Trp Ile Ser Arg Asp Ala Ala Gln Lys Ile Tyr Val Glu Met Lys 95 100105 Phe Thr Leu Arg Asp Cys Asn Ser Ile Pro Trp Val Leu Gly Thr 110 115120 Cys Lys Glu Thr Phe Asn Leu Phe Tyr Met Glu Ser Asp Glu Ser 125 130135 His Gly Ile Lys Phe Lys Pro Asn Gln Tyr Thr Lys Ile Asp Thr 140 145150 Ile Ala Ala Asp Glu Ser Phe Thr Gln Met Asp Leu Gly Asp Arg 155 160165 Ile Leu Lys Leu Asn Thr Glu Ile Arg Glu Val Gly Pro Ile Glu 170 175180 Arg Lys Gly Phe Tyr Leu Ala Phe Gln Asp Ile Gly Ala Cys Ile 185 190195 Ala Leu Val Ser Val Arg Val Phe Tyr Lys Lys Cys Pro Phe Thr 200 205210 Val Arg Asn Leu Ala Met Phe Pro Asp Thr Ile Pro Arg Val Asp 215 220225 Ser Ser Ser Leu Val Glu Val Arg Gly Ser Cys Val Lys Ser Ala 230 235240 Glu Glu Arg Asp Thr Pro Lys Leu Tyr Cys Gly Ala Asp Gly Asp 245 250255 Trp Leu Val Pro Leu Gly Arg Cys Ile Cys Ser Thr Gly Tyr Glu 260 265270 Glu Ile Glu Gly Ser Cys His Ala Cys Arg Pro Gly Phe Tyr Lys 275 280285 Ala Phe Ala Gly Asn Thr Lys Cys Ser Lys Cys Pro Pro His Ser 290 295300 Leu Thr Tyr Met Glu Ala Thr Ser Val Cys Gln Cys Glu Lys Gly 305 310315 Tyr Phe Arg Ala Glu Lys Asp Pro Pro Ser Met Ala Cys Thr Arg 320 325330 Pro Pro Ser Ala Pro Arg Asn Val Val Phe Asn Ile Asn Glu Thr 335 340345 Ala Leu Ile Leu Glu Trp Ser Pro Pro Ser Asp Thr Gly Gly Arg 350 355360 Lys Asp Leu Thr Tyr Ser Val Ile Cys Lys Lys Cys Gly Leu Asp 365 370375 Thr Ser Gln Cys Glu Asp Cys Gly Gly Gly Leu Arg Phe Ile Pro 380 385390 Arg His Thr Gly Leu Ile Asn Asn Ser Val Ile Val Leu Asp Phe 395 400405 Val Ser His Val Asn Tyr Thr Phe Glu Ile Glu Ala Met Asn Gly 410 415420 Val Ser Glu Leu Ser Phe Ser Pro Lys Pro Phe Thr Ala Ile Thr 425 430435 Val Thr Thr Asp Gln Asp Ala Pro Ser Leu Ile Gly Val Val Arg 440 445450 Lys Asp Trp Ala Ser Gln Asn Ser Ile Ala Leu Ser Trp Gln Ala 455 460465 Pro Ala Phe Ser Asn Gly Ala Ile Leu Asp Tyr Glu Ile Lys Tyr 470 475480 Tyr Glu Lys Glu His Glu Gln Leu Thr Tyr Ser Ser Thr Arg Ser 485 490495 Lys Ala Pro Ser Val Ile Ile Thr Gly Leu Lys Pro Ala Thr Lys 500 505510 Tyr Val Phe His Ile Arg Val Arg Thr Ala Thr Gly Tyr Ser Gly 515 520525 Tyr Ser Gln Lys Phe Glu Phe Glu Thr Gly Asp Glu Thr Ser Asp 530 535540 Met Ala Ala Glu Gln Gly Gln Ile Leu Val Ile Ala Thr Ala Ala 545 550555 Val Gly Gly Phe Thr Leu Leu Val Ile Leu Thr Leu Phe Phe Leu 560 565570 Ile Thr Gly Arg Cys Gln Trp Tyr Ile Lys Ala Lys Met Lys Ser 575 580585 Glu Glu Lys Arg Arg Asn His Leu Gln Asn Gly His Leu Arg Phe 590 595600 Pro Gly Ile Lys Thr Tyr Ile Asp Pro Asp Thr Tyr Glu Asp Pro 605 610615 Ser Leu Ala Val His Glu Phe Ala Lys Glu Ile Asp Pro Ser Arg 620 625630 Ile Arg Ile Glu Arg Val Ile Gly Ala Gly Glu Phe Gly Glu Val 635 640645 Cys Ser Gly Arg Leu Lys Thr Pro Gly Lys Arg Glu Ile Pro Val 650 655660 Ala Ile Lys Thr Leu Lys Gly Gly His Met Asp Arg Gln Arg Arg 665 670675 Asp Phe Leu Arg Glu Ala Ser Ile Met Gly Gln Phe Asp His Pro 680 685690 Asn Ile Ile Arg Leu Glu Gly Val Val Thr Lys Arg Ser Phe Pro 695 700705 Ala Ile Gly Val Glu Ala Phe Cys Pro Ser Phe Leu Arg Ala Gly 710 715720 Phe Leu Asn Ser Ile Gln Ala Pro His Pro Val Pro Gly Gly Gly 725 730735 Ser Leu Pro Pro Arg Ile Pro Ala Gly Arg Pro Val Met Ile Val 740 745750 Val Glu Tyr Met Glu Asn Gly Ser Leu Asp Ser Phe Leu Arg Lys 755 760765 His Asp Gly His Phe Thr Val Ile Gln Leu Val Gly Met Leu Arg 770 775780 Gly Ile Ala Ser Gly Met Lys Tyr Leu Ser Asp Met Gly Tyr Val 785 790795 His Arg Asp Leu Ala Ala Arg Asn Ile Leu Val Asn Ser Asn Leu 800 805810 Val Cys Lys Val Ser Asp Phe Gly Leu Ser Arg Val Leu Glu Asp 815 820825 Asp Pro Glu Ala Ala Tyr Thr Thr Thr Gly Gly Lys Ile Pro Ile 830 835840 Arg Trp Thr Ala Pro Glu Ala Ile Ala Tyr Arg Lys Phe Ser Ser 845 850855 Ala Ser Asp Ala Trp Ser Tyr Gly Ile Val Met Trp Glu Val Met 860 865870 Ser Tyr Gly Glu Arg Pro Tyr Trp Glu Met Ser Asn Gln Asp Val 875 880885 Ile Leu Ser Ile Glu Glu Gly Tyr Arg Leu Pro Ala Pro Met Gly 890 895900 Cys Pro Ala Ser Leu His Gln Leu Met Leu His Cys Trp Gln Lys 905 910915 Glu Arg Asn His Arg Pro Lys Phe Thr Asp Ile Val Ser Phe Leu 920 925930 Asp Lys Leu Ile Arg Asn Pro Ser Ala Leu His Thr Leu Val Glu 935 940945 Asp Ile Leu Val Met Pro Glu Ser Pro Gly Glu Val Pro Glu Tyr 950 955960 Pro Leu Phe Val Thr Val Gly Asp Trp Leu Asp Ser Ile Lys Met 965 970975 Gly Gln Tyr Lys Asn Asn Phe Val Ala Ala Gly Phe Thr Thr Phe 980 985990 Asp Leu Ile Ser Arg Met Ser Ile Asp Asp Ile Arg Arg Ile Gly 995 10001005 Val Ile Leu Ile Gly His Gln Arg Arg Ile Val Ser Ser Ile Gln 10101015 1020 Thr Leu Arg Leu His Met Met His Ile Gln Glu Lys Gly Phe His1025 1030 1035 Val 105 2148 DNA Homo Sapien 105 ggcggcgggc tgcgcggagcggcgtcccct gcagccgcgg accgaggcag 50 cggcggcacc tgccggccga gcaatgccaagtgagtacac ctatgtgaaa 100 ctgagaagtg attgctcgag gccttccctg caatggtacacccgagctca 150 aagcaagatg agaaggccca gcttgttatt aaaagacatc ctcaaatgta200 cattgcttgt gtttggagtg tggatccttt atatcctcaa gttaaattat 250actactgaag aatgtgacat gaaaaaaatg cattatgtgg accctgacca 300 tgtaaagagagctcagaaat atgctcagca agtcttgcag aaggaatgtc 350 gtcccaagtt tgccaagacatcaatggcgc tgttatttga gcacaggtat 400 agcgtggact tactcccttt tgtgcagaaggcccccaaag acagtgaagc 450 tgagtccaag tacgatcctc cttttgggtt ccggaagttctccagtaaag 500 tccagaccct cttggaactc ttgccagagc acgacctccc tgaacacttg550 aaagccaaga cctgtcggcg ctgtgtggtt attggaagcg gaggaatact 600gcacggatta gaactgggcc acaccctgaa ccagttcgat gttgtgataa 650 ggttaaacagtgcaccagtt gagggatatt cagaacatgt tggaaataaa 700 actactataa ggatgacttatccagagggc gcaccactgt ctgaccttga 750 atattattcc aatgacttat ttgttgctgttttatttaag agtgttgatt 800 tcaactggct tcaagcaatg gtaaaaaagg aaaccctgccattctgggta 850 cgactcttct tttggaagca ggtggcagaa aaaatcccac tgcagccaaa900 acatttcagg attttgaatc cagttatcat caaagagact gcctttgaca 950tccttcagta ctcagagcct cagtcaaggt tctggggccg agataagaac 1000 gtccccacaatcggtgtcat tgccgttgtc ttagccacac atctgtgcga 1050 tgaagtcagt ttggcgggttttggatatga cctcaatcaa cccagaacac 1100 ctttgcacta cttcgacagt caatgcatggctgctatgaa ctttcagacc 1150 atgcataatg tgacaacgga aaccaagttc ctcttaaagctggtcaaaga 1200 gggagtggtg aaagatctca gtggaggcat tgatcgtgaa ttttgaacac1250 agaaaacctc agttgaaaat gcaactctaa ctctgagagc tgtttttgac 1300agccttcttg atgtatttct ccatcctgca gatactttga agtgcagctc 1350 atgtttttaacttttaattt aaaaacacaa aaaaaatttt agctcttccc 1400 actttttttt tcctatttatttgaggtcag tgtttgtttt tgcacaccat 1450 tttgtaaatg aaacttaaga attgaattggaaagacttct caaagagaat 1500 tgtatgtaac gatgttgtat tgatttttaa gaaagtaatttaatttgtaa 1550 aacttctgct cgtttacact gcacattgaa tacaggtaac taattggaag1600 gagaggggag gtcactcttt tgatggtggc cctgaacctc attctggttc 1650cctgctgcgc tgcttggtgt gacccacgga ggatccactc ccaggatgac 1700 gtgctccgtagctctgctgc tgatactggg tctgcgatgc agcggcgtga 1750 ggcctgggct ggttggagaaggtcacaacc cttctctgtt ggtctgcctt 1800 ctgctgaaag actcgagaac caaccagggaagctgtcctg gaggtccctg 1850 gtcggagagg gacatagaat ctgtgacctc tgacaactgtgaagccaccc 1900 tgggctacag aaaccacagt cttcccagca attattacaa ttcttgaatt1950 ccttggggat tttttactgc cctttcaaag cacttaagtg ttagatctaa 2000cgtgttccag tgtctgtctg aggtgactta aaaaatcaga acaaaacttc 2050 tattatccagagtcatggga gagtacaccc tttccaggaa taatgttttg 2100 ggaaacactg aaatgaaatcttcccagtat tataaattgt gtatttaa 2148 106 362 PRT Homo Sapien 106 Met ArgArg Pro Ser Leu Leu Leu Lys Asp Ile Leu Lys Cys Thr 1 5 10 15 Leu LeuVal Phe Gly Val Trp Ile Leu Tyr Ile Leu Lys Leu Asn 20 25 30 Tyr Thr ThrGlu Glu Cys Asp Met Lys Lys Met His Tyr Val Asp 35 40 45 Pro Asp His ValLys Arg Ala Gln Lys Tyr Ala Gln Gln Val Leu 50 55 60 Gln Lys Glu Cys ArgPro Lys Phe Ala Lys Thr Ser Met Ala Leu 65 70 75 Leu Phe Glu His Arg TyrSer Val Asp Leu Leu Pro Phe Val Gln 80 85 90 Lys Ala Pro Lys Asp Ser GluAla Glu Ser Lys Tyr Asp Pro Pro 95 100 105 Phe Gly Phe Arg Lys Phe SerSer Lys Val Gln Thr Leu Leu Glu 110 115 120 Leu Leu Pro Glu His Asp LeuPro Glu His Leu Lys Ala Lys Thr 125 130 135 Cys Arg Arg Cys Val Val IleGly Ser Gly Gly Ile Leu His Gly 140 145 150 Leu Glu Leu Gly His Thr LeuAsn Gln Phe Asp Val Val Ile Arg 155 160 165 Leu Asn Ser Ala Pro Val GluGly Tyr Ser Glu His Val Gly Asn 170 175 180 Lys Thr Thr Ile Arg Met ThrTyr Pro Glu Gly Ala Pro Leu Ser 185 190 195 Asp Leu Glu Tyr Tyr Ser AsnAsp Leu Phe Val Ala Val Leu Phe 200 205 210 Lys Ser Val Asp Phe Asn TrpLeu Gln Ala Met Val Lys Lys Glu 215 220 225 Thr Leu Pro Phe Trp Val ArgLeu Phe Phe Trp Lys Gln Val Ala 230 235 240 Glu Lys Ile Pro Leu Gln ProLys His Phe Arg Ile Leu Asn Pro 245 250 255 Val Ile Ile Lys Glu Thr AlaPhe Asp Ile Leu Gln Tyr Ser Glu 260 265 270 Pro Gln Ser Arg Phe Trp GlyArg Asp Lys Asn Val Pro Thr Ile 275 280 285 Gly Val Ile Ala Val Val LeuAla Thr His Leu Cys Asp Glu Val 290 295 300 Ser Leu Ala Gly Phe Gly TyrAsp Leu Asn Gln Pro Arg Thr Pro 305 310 315 Leu His Tyr Phe Asp Ser GlnCys Met Ala Ala Met Asn Phe Gln 320 325 330 Thr Met His Asn Val Thr ThrGlu Thr Lys Phe Leu Leu Lys Leu 335 340 345 Val Lys Glu Gly Val Val LysAsp Leu Ser Gly Gly Ile Asp Arg 350 355 360 Glu Phe 107 1399 DNA HomoSapien 107 tgacgcgggg cgccagctgc caacttcgcg cgcggagctc cccggcggtg 50cagtcccgtc ccggcggcgc gggcggcatg aagactagcc gccgcggccg 100 agcgctcctggccgtggccc tgaacctgct ggcgctgctg ttcgccacca 150 ccgctttcct caccacgcactggtgccagg gcacgcagcg ggtccccaag 200 ccgggctgcg gccagggcgg gcgcgccaactgccccaact cgggcgccaa 250 cgccacggcc aacggcaccg ccgcccccgc cgccgccgccgccgccgcca 300 ccgcctcggg gaacggcccc cctggcggcg cgctctacag ctgggagacc350 ggcgacgacc gcttcctctt caggaatttc cacaccggca tctggtactc 400gtgcgaggag gagctcagcg ggcttggtga aaaatgtcgc agcttcattg 450 acctggccccggcgtcggag aaaggcctcc tgggaatggt cgcccacatg 500 atgtacacgc aggtgttccaggtcaccgtg agcctcggtc ctgaggactg 550 gagaccccat tcctgggact acgggtggtccttctgcctg gcgtggggct 600 cctttacctg ctgcatggca gcctctgtca ccacgctcaactcctacacc 650 aagacggtca ttgagttccg gcacaagcgc aaggtctttg agcagggcta700 ccgggaagag ccgaccttca tagaccctga ggccatcaag tacttccggg 750agaggatgga gaagagggac gggagcgagg aggactttca cttagactgc 800 cgccacgagagataccctgc ccgacaccag ccacacatgg cggattcctg 850 gccccggagc tccgcacaggaagcaccaga gctgaaccga cagtgctggg 900 tcttggggca ctgggtgtga ccaagacctcaacctggccc gcggacctca 950 ggccatcgct ggcaccagcc cctgctgcaa gaccaccagagtggtgcccc 1000 cagaaccctg gcctgtgtgc cgtgaactca gtcagcctgc gtgggagatg1050 ccaggcctgt cctgcccatc gctgcctggg tcccatggcc ttggaaatgg 1100ggccagggca ggcccaaggg aatgcacagg gctgcacaga gtgactttgg 1150 gacagcagccccggactctt gccatcatca catgagccct gctgggcaca 1200 gctgcgatgc caggagacacatggccactg gccactgaat ggctggcacc 1250 cacaagccag tcaggtgccc agaggggcagagccctttgg ggggcagaga 1300 gtggcttcct gaaggagggg gcagtggcgc aggcactgcaggggtgtcac 1350 acagcaggca cacagcaggg gctcaataaa tgcttgttga acttgtttt1399 108 280 PRT Homo Sapien 108 Met Lys Thr Ser Arg Arg Gly Arg Ala LeuLeu Ala Val Ala Leu 1 5 10 15 Asn Leu Leu Ala Leu Leu Phe Ala Thr ThrAla Phe Leu Thr Thr 20 25 30 His Trp Cys Gln Gly Thr Gln Arg Val Pro LysPro Gly Cys Gly 35 40 45 Gln Gly Gly Arg Ala Asn Cys Pro Asn Ser Gly AlaAsn Ala Thr 50 55 60 Ala Asn Gly Thr Ala Ala Pro Ala Ala Ala Ala Ala AlaAla Thr 65 70 75 Ala Ser Gly Asn Gly Pro Pro Gly Gly Ala Leu Tyr Ser TrpGlu 80 85 90 Thr Gly Asp Asp Arg Phe Leu Phe Arg Asn Phe His Thr Gly Ile95 100 105 Trp Tyr Ser Cys Glu Glu Glu Leu Ser Gly Leu Gly Glu Lys Cys110 115 120 Arg Ser Phe Ile Asp Leu Ala Pro Ala Ser Glu Lys Gly Leu Leu125 130 135 Gly Met Val Ala His Met Met Tyr Thr Gln Val Phe Gln Val Thr140 145 150 Val Ser Leu Gly Pro Glu Asp Trp Arg Pro His Ser Trp Asp Tyr155 160 165 Gly Trp Ser Phe Cys Leu Ala Trp Gly Ser Phe Thr Cys Cys Met170 175 180 Ala Ala Ser Val Thr Thr Leu Asn Ser Tyr Thr Lys Thr Val Ile185 190 195 Glu Phe Arg His Lys Arg Lys Val Phe Glu Gln Gly Tyr Arg Glu200 205 210 Glu Pro Thr Phe Ile Asp Pro Glu Ala Ile Lys Tyr Phe Arg Glu215 220 225 Arg Met Glu Lys Arg Asp Gly Ser Glu Glu Asp Phe His Leu Asp230 235 240 Cys Arg His Glu Arg Tyr Pro Ala Arg His Gln Pro His Met Ala245 250 255 Asp Ser Trp Pro Arg Ser Ser Ala Gln Glu Ala Pro Glu Leu Asn260 265 270 Arg Gln Cys Trp Val Leu Gly His Trp Val 275 280 109 2964 DNAHomo Sapien 109 gattaccaag caagaacagc taaaatgaaa gccatcattc atcttactct50 tcttgctctc ctttctgtaa acacagccac caaccaaggc aactcagctg 100 atgctgtaacaaccacagaa actgcgacta gtggtcctac agtagctgca 150 gctgatacca ctgaaactaatttccctgaa actgctagca ccacagcaaa 200 tacaccttct ttcccaacag ctacttcacctgctcccccc ataattagta 250 cacatagttc ctccacaatt cctacacctg ctccccccataattagtaca 300 catagttcct ccacaattcc tatacctact gctgcagaca gtgagtcaac350 cacaaatgta aattcattag ctacctctga cataatcacc gcttcatctc 400caaatgatgg attaatcaca atggttcctt ctgaaacaca aagtaacaat 450 gaaatgtcccccaccacaga agacaatcaa tcatcagggc ctcccactgg 500 caccgcttta ttggagaccagcaccctaaa cagcacaggt cccagcaatc 550 cttgccaaga tgatccctgt gcagataattcgttatgtgt taagctgcat 600 aatacaagtt tttgcctgtg tttagaaggg tattactacaactcttctac 650 atgtaagaaa ggaaaggtat tccctgggaa gatttcagtg acagtatcag700 aaacatttga cccagaagag aaacattcca tggcctatca agacttgcat 750agtgaaatta ctagcttgtt taaagatgta tttggcacat ctgtttatgg 800 acagactgtaattcttactg taagcacatc tctgtcacca agatctgaaa 850 tgcgtgctga tgacaagtttgttaatgtaa caatagtaac aattttggca 900 gaaaccacaa gtgacaatga gaagactgtgactgagaaaa ttaataaagc 950 aattagaagt agctcaagca actttctaaa ctatgatttgacccttcggt 1000 gtgattatta tggctgtaac cagactgcgg atgactgcct caatggttta1050 gcatgcgatt gcaaatctga cctgcaaagg cctaacccac agagcccttt 1100ctgcgttgct tccagtctca agtgtcctga tgcctgcaac gcacagcaca 1150 agcaatgcttaataaagaag agtggtgggg cccctgagtg tgcgtgcgtg 1200 cccggctacc aggaagatgctaatgggaac tgccaaaagt gtgcatttgg 1250 ctacagtgga ctcgactgta aggacaaatttcagctgatc ctcactattg 1300 tgggcaccat cgctggcatt gtcattctca gcatgataattgcattgatt 1350 gtcacagcaa gatcaaataa caaaacgaag catattgaag aagagaactt1400 gattgacgaa gactttcaaa atctaaaact gcggtcgaca ggcttcacca 1450atcttggagc agaagggagc gtctttccta aggtcaggat aacggcctcc 1500 agagacagccagatgcaaaa tccctattca agccacagca gcatgccccg 1550 ccctgactat tagaatcataagaatgtgga acccgccatg gcccccaacc 1600 aatgtacaag ctattattta gagtgtttagaaagactgat ggagaagtga 1650 gcaccagtaa agatctggcc tccggggttt ttcttccatctgacatctgc 1700 cagcctctct gaatggaagt tgtgaatgtt tgcaacgaat ccagctcact1750 tgctaaataa gaatctatga cattaaatgt agtagatgct attagcgctt 1800gtcagagagg tggttttctt caatcagtac aaagtactga gacaatggtt 1850 agggttgttttcttaattct tttcctggta gggcaacaag aaccatttcc 1900 aatctagagg aaagctccccagcattgctt gctcctgggc aaacattgct 1950 cttgagttaa gtgacctaat tcccctgggagacatacgca tcaactgtgg 2000 aggtccgagg ggatgagaag ggatacccac catctttcaagggtcacaag 2050 ctcactctct gacaagtcag aatagggaca ctgcttctat ccctccaatg2100 gagagattct ggcaaccttt gaacagccca gagcttgcaa cctagcctca 2150cccaagaaga ctggaaagag acatatctct cagctttttc aggaggcgtg 2200 cctgggaatccaggaacttt ttgatgctaa ttagaaggcc tggactaaaa 2250 atgtccacta tggggtgcactctacagttt ttgaaatgct aggaggcaga 2300 aggggcagag agtaaaaaac atgacctggtagaaggaaga gaggcaaagg 2350 aaactgggtg gggaggatca attagagagg aggcacctgggatccacctt 2400 cttccttagg tcccctcctc catcagcaaa ggagcacttc tctaatcatg2450 ccctcccgaa gactggctgg gagaaggttt aaaaacaaaa aatccaggag 2500taagagcctt aggtcagttt gaaattggag acaaactgtc tggcaaaggg 2550 tgcgagagggagcttgtgct caggagtcca gccgcccagc ctcggggtgt 2600 aggtttctga ggtgtgccattggggcctca gccttctctg gtgacagagg 2650 ctcagctgtg gccaccaaca cacaaccacacacacacaac cacacacaca 2700 aatgggggca accacatcca gtacaagctt ttacaaatgttattagtgtc 2750 cttttttatt tctaatgcct tgtcctctta aaagttattt tatttgttat2800 tattatttgt tcttgactgt taattgtgaa tggtaatgca ataaagtgcc 2850tttgttagat ggtgaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2900 aaaaaaaaaaaaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2950 aaaaaaaaaa aaaa 2964110 512 PRT Homo Sapien 110 Met Lys Ala Ile Ile His Leu Thr Leu Leu AlaLeu Leu Ser Val 1 5 10 15 Asn Thr Ala Thr Asn Gln Gly Asn Ser Ala AspAla Val Thr Thr 20 25 30 Thr Glu Thr Ala Thr Ser Gly Pro Thr Val Ala AlaAla Asp Thr 35 40 45 Thr Glu Thr Asn Phe Pro Glu Thr Ala Ser Thr Thr AlaAsn Thr 50 55 60 Pro Ser Phe Pro Thr Ala Thr Ser Pro Ala Pro Pro Ile IleSer 65 70 75 Thr His Ser Ser Ser Thr Ile Pro Thr Pro Ala Pro Pro Ile Ile80 85 90 Ser Thr His Ser Ser Ser Thr Ile Pro Ile Pro Thr Ala Ala Asp 95100 105 Ser Glu Ser Thr Thr Asn Val Asn Ser Leu Ala Thr Ser Asp Ile 110115 120 Ile Thr Ala Ser Ser Pro Asn Asp Gly Leu Ile Thr Met Val Pro 125130 135 Ser Glu Thr Gln Ser Asn Asn Glu Met Ser Pro Thr Thr Glu Asp 140145 150 Asn Gln Ser Ser Gly Pro Pro Thr Gly Thr Ala Leu Leu Glu Thr 155160 165 Ser Thr Leu Asn Ser Thr Gly Pro Ser Asn Pro Cys Gln Asp Asp 170175 180 Pro Cys Ala Asp Asn Ser Leu Cys Val Lys Leu His Asn Thr Ser 185190 195 Phe Cys Leu Cys Leu Glu Gly Tyr Tyr Tyr Asn Ser Ser Thr Cys 200205 210 Lys Lys Gly Lys Val Phe Pro Gly Lys Ile Ser Val Thr Val Ser 215220 225 Glu Thr Phe Asp Pro Glu Glu Lys His Ser Met Ala Tyr Gln Asp 230235 240 Leu His Ser Glu Ile Thr Ser Leu Phe Lys Asp Val Phe Gly Thr 245250 255 Ser Val Tyr Gly Gln Thr Val Ile Leu Thr Val Ser Thr Ser Leu 260265 270 Ser Pro Arg Ser Glu Met Arg Ala Asp Asp Lys Phe Val Asn Val 275280 285 Thr Ile Val Thr Ile Leu Ala Glu Thr Thr Ser Asp Asn Glu Lys 290295 300 Thr Val Thr Glu Lys Ile Asn Lys Ala Ile Arg Ser Ser Ser Ser 305310 315 Asn Phe Leu Asn Tyr Asp Leu Thr Leu Arg Cys Asp Tyr Tyr Gly 320325 330 Cys Asn Gln Thr Ala Asp Asp Cys Leu Asn Gly Leu Ala Cys Asp 335340 345 Cys Lys Ser Asp Leu Gln Arg Pro Asn Pro Gln Ser Pro Phe Cys 350355 360 Val Ala Ser Ser Leu Lys Cys Pro Asp Ala Cys Asn Ala Gln His 365370 375 Lys Gln Cys Leu Ile Lys Lys Ser Gly Gly Ala Pro Glu Cys Ala 380385 390 Cys Val Pro Gly Tyr Gln Glu Asp Ala Asn Gly Asn Cys Gln Lys 395400 405 Cys Ala Phe Gly Tyr Ser Gly Leu Asp Cys Lys Asp Lys Phe Gln 410415 420 Leu Ile Leu Thr Ile Val Gly Thr Ile Ala Gly Ile Val Ile Leu 425430 435 Ser Met Ile Ile Ala Leu Ile Val Thr Ala Arg Ser Asn Asn Lys 440445 450 Thr Lys His Ile Glu Glu Glu Asn Leu Ile Asp Glu Asp Phe Gln 455460 465 Asn Leu Lys Leu Arg Ser Thr Gly Phe Thr Asn Leu Gly Ala Glu 470475 480 Gly Ser Val Phe Pro Lys Val Arg Ile Thr Ala Ser Arg Asp Ser 485490 495 Gln Met Gln Asn Pro Tyr Ser Ser His Ser Ser Met Pro Arg Pro 500505 510 Asp Tyr 111 943 DNA Homo Sapien 111 ctgggacttg gctttctccggataagcggc ggcaccggcg tcagcgatga 50 ccgtgcagag actcgtggcc gcggccgtgctggtggccct ggtctcactc 100 atcctcaaca acgtggcggc cttcacctcc aactgggtgtgccagacgct 150 ggaggatggg cgcaggcgca gcgtggggct gtggaggtcc tgctggctgg200 tggacaggac ccggggaggg ccgagccctg gggccagagc cggccaggtg 250gacgcacatg actgtgaggc gctgggctgg ggctccgagg cagccggctt 300 ccaggagtcccgaggcaccg tcaaactgca gttcgacatg atgcgcgcct 350 gcaacctggt ggccacggccgcgctcaccg caggccagct caccttcctc 400 ctggggctgg tgggcctgcc cctgctgtcacccgacgccc cgtgctggga 450 ggaggccatg gccgctgcat tccaactggc gagttttgtcctggtcatcg 500 ggctcgtgac tttctacaga attggcccat acaccaacct gtcctggtcc550 tgctacctga acattggcgc ctgccttctg gccacgctgg cggcagccat 600gctcatctgg aacattctcc acaagaggga ggactgcatg gccccccggg 650 tgattgtcatcagccgctcc ctgacagcgc gctttcgccg tgggctggac 700 aatgactacg tggagtcaccatgctgagtc gcccttctca gcgctccatc 750 aacgcacacc tgctatcgtg gaacagcctagaaaccaagg gactccacca 800 ccaagtcact tcccctgctc gtgcagaggc acgggatgagtctgggtgac 850 ctctgcgcca tgcgtgcgag acacgtgtgc gtttactgtt atgtcggtca900 tatgtctgta cgtgtcgtgg gccaacctcg ttctgcctcc agc 943 112 226 PRT HomoSapien 112 Met Thr Val Gln Arg Leu Val Ala Ala Ala Val Leu Val Ala Leu 15 10 15 Val Ser Leu Ile Leu Asn Asn Val Ala Ala Phe Thr Ser Asn Trp 2025 30 Val Cys Gln Thr Leu Glu Asp Gly Arg Arg Arg Ser Val Gly Leu 35 4045 Trp Arg Ser Cys Trp Leu Val Asp Arg Thr Arg Gly Gly Pro Ser 50 55 60Pro Gly Ala Arg Ala Gly Gln Val Asp Ala His Asp Cys Glu Ala 65 70 75 LeuGly Trp Gly Ser Glu Ala Ala Gly Phe Gln Glu Ser Arg Gly 80 85 90 Thr ValLys Leu Gln Phe Asp Met Met Arg Ala Cys Asn Leu Val 95 100 105 Ala ThrAla Ala Leu Thr Ala Gly Gln Leu Thr Phe Leu Leu Gly 110 115 120 Leu ValGly Leu Pro Leu Leu Ser Pro Asp Ala Pro Cys Trp Glu 125 130 135 Glu AlaMet Ala Ala Ala Phe Gln Leu Ala Ser Phe Val Leu Val 140 145 150 Ile GlyLeu Val Thr Phe Tyr Arg Ile Gly Pro Tyr Thr Asn Leu 155 160 165 Ser TrpSer Cys Tyr Leu Asn Ile Gly Ala Cys Leu Leu Ala Thr 170 175 180 Leu AlaAla Ala Met Leu Ile Trp Asn Ile Leu His Lys Arg Glu 185 190 195 Asp CysMet Ala Pro Arg Val Ile Val Ile Ser Arg Ser Leu Thr 200 205 210 Ala ArgPhe Arg Arg Gly Leu Asp Asn Asp Tyr Val Glu Ser Pro 215 220 225 Cys 1131389 DNA Homo Sapien 113 gactttacca ctactcgcta tagagccctg gtcaagttctctccacctct 50 ctatctatgt ctcagtttct tcatctgtaa catcaaatga ataataatac 100caatctccta gacttcataa gaggattaac aaagacaaaa tatgggaaaa 150 acataacatggcgtcccata attattagat cttattattg acactaaaat 200 ggcattaaaa ttaccaaaaggaagacagca tctgtttcct ctttggtcct 250 gagctggtta aaaggaacac tggttgcctgaacagtcaca cttgcaacca 300 tgatgcctaa acattgcttt ctaggcttcc tcatcagtttcttccttact 350 ggtgtagcag gaactcagtc aacgcatgag tctctgaagc ctcagagggt400 acaatttcag tcccgaaatt ttcacaacat tttgcaatgg cagcctggga 450gggcacttac tggcaacagc agtgtctatt ttgtgcagta caaaatatat 500 ggacagagacaatggaaaaa taaagaagac tgttggggta ctcaagaact 550 ctcttgtgac cttaccagtgaaacctcaga catacaggaa ccttattacg 600 ggagggtgag ggcggcctcg gctgggagctactcagaatg gagcatgacg 650 ccgcggttca ctccctggtg ggaaacaaaa atagatcctccagtcatgaa 700 tataacccaa gtcaatggct ctttgttggt aattctccat gctccaaatt750 taccatatag ataccaaaag gaaaaaaatg tatctataga agattactat 800gaactactat accgagtttt tataattaac aattcactag aaaaggagca 850 aaaggtttatgaaggggctc acagagcggt tgaaattgaa gctctaacac 900 cacactccag ctactgtgtagtggctgaaa tatatcagcc catgttagac 950 agaagaagtc agagaagtga agagagatgtgtggaaattc catgacttgt 1000 ggaatttggc attcagcaat gtggaaattc taaagctccctgagaacagg 1050 atgactcgtg tttgaaggat cttatttaaa attgtttttg tattttctta1100 aagcaatatt cactgttaca ccttggggac ttctttgttt acccattctt 1150ttatccttta tatttcattt gtaaactata tttgaacgac attccccccg 1200 aaaaattgaaatgtaaagat gaggcagaga ataaagtgtt ctatgaaatt 1250 cagaacttta tttctgaatgtaacatccct aataacaacc ttcattcttc 1300 taatacagca aaataaaaat ttaacaaccaaggaatagta tttaagaaaa 1350 tgttgaaata atttttttaa aatagcatta cagactgag1389 114 231 PRT Homo Sapien 114 Met Met Pro Lys His Cys Phe Leu Gly PheLeu Ile Ser Phe Phe 1 5 10 15 Leu Thr Gly Val Ala Gly Thr Gln Ser ThrHis Glu Ser Leu Lys 20 25 30 Pro Gln Arg Val Gln Phe Gln Ser Arg Asn PheHis Asn Ile Leu 35 40 45 Gln Trp Gln Pro Gly Arg Ala Leu Thr Gly Asn SerSer Val Tyr 50 55 60 Phe Val Gln Tyr Lys Ile Tyr Gly Gln Arg Gln Trp LysAsn Lys 65 70 75 Glu Asp Cys Trp Gly Thr Gln Glu Leu Ser Cys Asp Leu ThrSer 80 85 90 Glu Thr Ser Asp Ile Gln Glu Pro Tyr Tyr Gly Arg Val Arg Ala95 100 105 Ala Ser Ala Gly Ser Tyr Ser Glu Trp Ser Met Thr Pro Arg Phe110 115 120 Thr Pro Trp Trp Glu Thr Lys Ile Asp Pro Pro Val Met Asn Ile125 130 135 Thr Gln Val Asn Gly Ser Leu Leu Val Ile Leu His Ala Pro Asn140 145 150 Leu Pro Tyr Arg Tyr Gln Lys Glu Lys Asn Val Ser Ile Glu Asp155 160 165 Tyr Tyr Glu Leu Leu Tyr Arg Val Phe Ile Ile Asn Asn Ser Leu170 175 180 Glu Lys Glu Gln Lys Val Tyr Glu Gly Ala His Arg Ala Val Glu185 190 195 Ile Glu Ala Leu Thr Pro His Ser Ser Tyr Cys Val Val Ala Glu200 205 210 Ile Tyr Gln Pro Met Leu Asp Arg Arg Ser Gln Arg Ser Glu Glu215 220 225 Arg Cys Val Glu Ile Pro 230 115 43 DNA Artificial SequenceSynthetic Oligonucleotide Probe 115 tgtaaaacga cggccagtta aatagacctgcaattattaa tct 43 116 41 DNA Artificial Sequence SyntheticOligonucleotide Probe 116 caggaaacag ctatgaccac ctgcacacct gcaaatccat t41

What is claimed is:
 1. Isolated nucleic acid having at least 80% nucleicacid sequence identity to a nucleotide sequence that encodes an aminoacid sequence selected from the group consisting of the amino acidsequence shown in FIG. 2 (SEQ ID NO:2), FIG. 4 (SEQ ID NO:4), FIG. 6(SEQ ID NO:6), FIG. 8 (SEQ ID NO:8), FIG. 10 (SEQ ID NO:10), FIG. 12(SEQ ID NO:12), FIG. 14 (SEQ ID NO:14), FIG. 16 (SEQ ID NO:16), FIG. 18(SEQ ID NO:18), FIG. 20 (SEQ ID NO:20), FIG. 22 (SEQ ID NO:22), FIG. 24(SEQ ID NO:24), FIG. 26 (SEQ ID NO:26), FIG. 28 (SEQ ID NO:28), FIG. 30(SEQ ID NO:30), FIG. 32 (SEQ ID NO:32), FIG. 34 (SEQ ID NO:34), FIG. 36(SEQ ID NO:36), FIG. 38 (SEQ ID NO:38), FIG. 40 (SEQ ID NO:40), FIG. 42(SEQ ID NO:42), FIG. 44 (SEQ ID NO:44), FIG. 46 (SEQ ID NO:46), FIG. 48(SEQ ID NO:48), FIG. 50 (SEQ ID NO:50), FIG. 52 (SEQ ID NO:52), FIG. 54(SEQ ID NO:54), FIG. 56 (SEQ ID NO:56), FIG. 58 (SEQ ID NO:58), FIG. 60(SEQ ID NO:60), FIG. 62 (SEQ ID NO:62), FIG. 64 (SEQ ID NO:64), FIG. 66(SEQ ID NO:66), FIG. 68 (SEQ ID NO:68), FIG. 70 (SEQ ID NO:70), FIG. 72(SEQ ID NO:72), FIG. 74 (SEQ ID NO:74), FIG. 76 (SEQ ID NO:76), FIG. 78(SEQ ID NO:78), FIG. 80 (SEQ ID NO:80), FIG. 82 (SEQ ID NO:82), FIG. 84(SEQ ID NO:84), FIG. 86 (SEQ ID NO:86), FIG. 88 (SEQ ID NO:88), FIG. 90(SEQ ID NO:90), FIG. 92 (SEQ ID NO:92), FIG. 94 (SEQ ID NO:94), FIG. 96(SEQ ID NO:96), FIG. 98 (SEQ ID NO:98), FIG. 100 (SEQ ID NO:100), FIG.102 (SEQ ID NO:102), FIG. 104 (SEQ ID NO:104), FIG. 106 (SEQ ID NO:106),FIG. 108 (SEQ ID NO:108), FIG. 110 (SEQ ID NO:110), FIG. 112 (SEQ IDNO:112) and FIG. 114 (SEQ ID NO:114.
 2. Isolated nucleic acid having atleast 80% nucleic acid sequence identity to a nucleotide sequenceselected from the group consisting of the nucleotide sequence shown inFIG. 1 (SEQ ID NO:1), FIG. 3 (SEQ ID NO:3), FIG. 5 (SEQ ID NO:5), FIG. 7(SEQ ID NO:7), FIG. 9 (SEQ ID NO:9), FIG. 11 (SEQ ID NO:11), FIG. 13(SEQ ID NO:13), FIG. 15 (SEQ ID NO:15), FIG. 17 (SEQ ID NO:17), FIG. 19(SEQ ID NO:19), FIG. 21 (SEQ ID NO:21), FIG. 23 (SEQ ID NO:23), FIG. 25(SEQ ID NO:25), FIG. 27 (SEQ ID NO:27), FIG. 29 (SEQ ID NO:29), FIG. 31(SEQ ID NO:31), FIG. 33 (SEQ ID NO:33), FIG. 35 (SEQ ID NO:35), FIG. 37(SEQ ID NO:37), FIG. 39 (SEQ ID NO:39), FIG. 41 (SEQ ID NO:41), FIG. 43(SEQ ID NO:43), FIG. 45 (SEQ ID NO:45), FIG. 47 (SEQ ID NO:47), FIG. 49(SEQ ID NO:49), FIG. 51 (SEQ ID NO:51), FIG. 53 (SEQ ID NO:53), FIG. 55(SEQ ID NO:55), FIG. 57 (SEQ ID NO:57), FIG. 59 (SEQ ID NO:59), FIG. 61(SEQ ID NO:61), FIG. 63 (SEQ ID NO:63), FIG. 65 (SEQ ID NO:65), FIG. 67(SEQ ID NO:67), FIG. 69 (SEQ ID NO:69), FIG. 71 (SEQ ID NO:71), FIG. 73(SEQ ID NO:73), FIG. 75 (SEQ ID NO:75), FIG. 77 (SEQ ID NO:77), FIG. 79(SEQ ID NO:79), FIG. 81 (SEQ ID NO:81), FIG. 83 (SEQ ID NO:83), FIG. 85(SEQ ID NO:85), FIG. 87 (SEQ ID NO:87), FIG. 89 (SEQ ID NO:89), FIG. 91(SEQ ID NO:91), FIG. 93 (SEQ ID NO:93), FIGS. 95A-95B (SEQ ID NO:95),FIG. 97 (SEQ ID NO:97), FIG. 99 (SEQ ID NO:99), FIG. 101 (SEQ IDNO:101), FIG. 103 (SEQ ID NO:103), FIG. 105 (SEQ ID NO:105), FIG. 107(SEQ ID NO:107), FIG. 109 (SEQ ID NO:109), FIG. 111 (SEQ ID NO:111) andFIG. 113 (SEQ ID NO:113).
 3. Isolated nucleic acid having at least 80%nucleic acid sequence identity to a nucleotide sequence selected fromthe group consisting of the full-length coding sequence of thenucleotide sequence shown in FIG. 1 (SEQ ID NO:1), FIG. 3 (SEQ ID NO:3),FIG. 5 (SEQ ID NO:5), FIG. 7 (SEQ ID NO:7), FIG. 9 (SEQ ID NO:9), FIG.11 (SEQ ID NO:11), FIG. 13 (SEQ ID NO:13), FIG. 15 (SEQ ID NO:15), FIG.17 (SEQ ID NO:17), FIG. 19 (SEQ ID NO:19), FIG. 21 (SEQ ID NO:21), FIG.23 (SEQ ID NO:23), FIG. 25 (SEQ ID NO:25), FIG. 27 (SEQ ID NO:27), FIG.29 (SEQ ID NO:29), FIG. 31 (SEQ ID NO:31), FIG. 33 (SEQ ID NO:33), FIG.35 (SEQ ID NO:35), FIG. 37 (SEQ ID NO:37), FIG. 39 (SEQ ID NO:39), FIG.41 (SEQ ID NO:41), FIG. 43 (SEQ ID NO:43), FIG. 45 (SEQ ID NO:45), FIG.47 (SEQ ID NO:47), FIG. 49 (SEQ ID NO:49), FIG. 51 (SEQ ID NO:51), FIG.53 (SEQ ID NO:53), FIG. 55 (SEQ ID NO:55), FIG. 57 (SEQ ID NO:57), FIG.59 (SEQ ID NO:59), FIG. 61 (SEQ ID NO:61), FIG. 63 (SEQ ID NO:63), FIG.65 (SEQ ID NO:65), FIG. 67 (SEQ ID NO:67), FIG. 69 (SEQ ID NO:69), FIG.71 (SEQ ID NO:71), FIG. 73 (SEQ ID NO:73), FIG. 75 (SEQ ID NO:75), FIG.77 (SEQ ID NO:77), FIG. 79 (SEQ ID NO:79), FIG. 81 (SEQ ID NO:81), FIG.83 (SEQ ID NO:83), FIG. 85 (SEQ ID NO:85), FIG. 87 (SEQ ID NO:87), FIG.89 (SEQ ID NO:89), FIG. 91 (SEQ ID NO:91), FIG. 93 (SEQ ID NO:93), FIGS.95A-95B (SEQ ID NO:95), FIG. 97 (SEQ ID NO:97), FIG. 99 (SEQ ID NO:99),FIG. 101 (SEQ ID NO:101), FIG. 103 (SEQ ID NO:103), FIG. 105 (SEQ IDNO:105), FIG. 107 (SEQ ID NO:107), FIG. 109 (SEQ ID NO:109), FIG. 111(SEQ ID NO:111) and FIG. 113 (SEQ ID NO:113).
 4. Isolated nucleic acidhaving at least 80% nucleic acid sequence identity to the full-lengthcoding sequence of the DNA deposited under any ATCC accession numbershown in Table
 7. 5. A vector comprising the nucleic acid of claim
 1. 6.A host cell comprising the vector of claim
 5. 7. The host cell of claim6, wherein said cell is a CHO cell.
 8. The host cell of claim 6, whereinsaid cell is an E. coli.
 9. The host cell of claim 6, wherein said cellis a yeast cell.
 10. A process for producing a PRO polypeptidecomprising culturing the host cell of claim 6 under conditions suitablefor expression of said PRO polypeptide and recovering said PROpolypeptide from the cell culture.
 11. An isolated polypeptide having atleast 80% amino acid sequence identity to an amino acid sequenceselected from the group consisting of the amino acid sequence shown inFIG. 2 (SEQ ID NO:2), FIG. 4 (SEQ ID NO:4), FIG. 6 (SEQ ID NO:6), FIG. 8(SEQ ID NO:8), FIG. 10 (SEQ ID NO:10), FIG. 12 (SEQ ID NO:12), FIG. 14(SEQ ID NO:14), FIG. 16 (SEQ ID NO:16), FIG. 18 (SEQ ID NO:18), FIG. 20(SEQ ID NO:20), FIG. 22 (SEQ ID NO:22), FIG. 24 (SEQ ID NO:24), FIG. 26(SEQ ID NO:26), FIG. 28 (SEQ ID NO:28), FIG. 30 (SEQ ID NO:30), FIG. 32(SEQ ID NO:32), FIG. 34 (SEQ ID NO:34), FIG. 36 (SEQ ID NO:36), FIG. 38(SEQ ID NO:38), FIG. 40 (SEQ ID NO:40), FIG. 42 (SEQ ID NO:42), FIG. 44(SEQ ID NO:44), FIG. 46 (SEQ ID NO:46), FIG. 48 (SEQ ID NO:48), FIG. 50(SEQ ID NO:50), FIG. 52 (SEQ ID NO:52), FIG. 54 (SEQ ID NO:54), FIG. 56(SEQ ID NO:56), FIG. 58 (SEQ ID NO:58), FIG. 60 (SEQ ID NO:60), FIG. 62(SEQ ID NO:62), FIG. 64 (SEQ ID NO:64), FIG. 66 (SEQ ID NO:66), FIG. 68(SEQ ID NO:68), FIG. 70 (SEQ ID NO:70), FIG. 72 (SEQ ID NO:72), FIG. 74(SEQ ID NO:74), FIG. 76 (SEQ ID NO:76), FIG. 78 (SEQ ID NO:78), FIG. 80(SEQ ID NO:80), FIG. 82 (SEQ ID NO:82), FIG. 84 (SEQ ID NO:84), FIG. 86(SEQ ID NO:86), FIG. 88 (SEQ ID NO:88), FIG. 90 (SEQ ID NO:90), FIG. 92(SEQ ID NO:92), FIG. 94 (SEQ ID NO:94), FIG. 96 (SEQ ID NO:96), FIG. 98(SEQ ID NO:98), FIG. 100 (SEQ ID NO:100), FIG. 102 (SEQ ID NO:102), FIG.104 (SEQ ID NO:104), FIG. 106 (SEQ ID NO:106), FIG. 108 (SEQ ID NO:108),FIG. 110 (SEQ ID NO:110), FIG. 112 (SEQ ID NO:112) and FIG. 114 (SEQ IDNO:114).
 12. An isolated polypeptide having at least 80% amino acidsequence identity to an amino acid sequence encoded by the full-lengthcoding sequence of the DNA deposited under any ATCC accession numbershown in Table
 7. 13. A chimeric molecule comprising a polypeptideaccording to claim 11 fused to a heterologous amino acid sequence. 14.The chimeric molecule of claim 13, wherein said heterologous amino acidsequence is an epitope tag sequence.
 15. The chimeric molecule of claim13, wherein said heterologous amino acid sequence is a Fc region of animmunoglobulin.
 16. An antibody which specifically binds to apolypeptide according to claim
 11. 17. The antibody of claim 16, whereinsaid antibody is a monoclonal antibody, a humanized antibody or asingle-chain antibody.
 18. Isolated nucleic acid having at least 80%nucleic acid sequence identity to: (a) a nucleotide sequence encodingthe polypeptide shown in FIG. 2 (SEQ ID NO:2), FIG. 4 (SEQ ID NO:4),FIG. 6 (SEQ ID NO:6), FIG. 8 (SEQ ID NO:8), FIG. 10 (SEQ ID NO:10), FIG.12 (SEQ ID NO:12), FIG. 14 (SEQ ID NO:14), FIG. 16 (SEQ ID NO:16), FIG.18 (SEQ ID NO:18), FIG. 20 (SEQ ID NO:20), FIG. 22 (SEQ ID NO:22), FIG.24 (SEQ ID NO:24), FIG. 26 (SEQ ID NO:26), FIG. 28 (SEQ ID NO:28), FIG.30 (SEQ ID NO:30), FIG. 32 (SEQ ID NO:32), FIG. 34 (SEQ ID NO:34), FIG.36 (SEQ ID NO:36), FIG. 38 (SEQ ID NO:38), FIG. 40 (SEQ ID NO:40), FIG.42 (SEQ ID NO:42), FIG. 44 (SEQ ID NO:44), FIG. 46 (SEQ ID NO:46), FIG.48 (SEQ ID NO:48), FIG. 50 (SEQ ID NO:50), FIG. 52 (SEQ ID NO:52), FIG.54 (SEQ ID NO:54), FIG. 56 (SEQ ID NO:56), FIG. 58 (SEQ ID NO:58), FIG.60 (SEQ ID NO:60), FIG. 62 (SEQ ID NO:62), FIG. 64 (SEQ ID NO:64), FIG.66 (SEQ ID NO:66), FIG. 68 (SEQ ID NO:68), FIG. 70 (SEQ ID NO:70), FIG.72 (SEQ ID NO:72), FIG. 74 (SEQ ID NO:74), FIG. 76 (SEQ ID NO:76), FIG.78 (SEQ ID NO:78), FIG. 80 (SEQ ID NO:80), FIG. 82 (SEQ ID NO:82), FIG.84 (SEQ ID NO:84), FIG. 86 (SEQ ID NO:86), FIG. 88 (SEQ ID NO:88), FIG.90 (SEQ ID NO:90), FIG. 92 (SEQ ID NO:92), FIG. 94 (SEQ ID NO:94), FIG.96 (SEQ ID NO:96), FIG. 98 (SEQ ID NO:98), FIG. 100 (SEQ ID NO: 100),FIG. 102 (SEQ ID NO:102), FIG. 104 (SEQ ID NO:104), FIG. 106 (SEQ IDNO:106), FIG. 108 (SEQ ID NO:108), FIG. 110 (SEQ ID NO:110), FIG. 112(SEQ ID NO:112) or FIG. 114 (SEQ ID NO:114), lacking its associatedsignal peptide; (b) a nucleotide sequence encoding an extracellulardomain of the polypeptide shown in FIG. 2 (SEQ ID NO:2), FIG. 4 (SEQ IDNO:4), FIG. 6 (SEQ ID NO:6), FIG. 8 (SEQ ID NO:8), FIG. 10 (SEQ IDNO:10), FIG. 12 (SEQ ID NO:12), FIG. 14 (SEQ ID NO:14), FIG. 16 (SEQ IDNO:16), FIG. 18 (SEQ ID NO:18), FIG. 20 (SEQ ID NO:20), FIG. 22 (SEQ IDNO:22), FIG. 24 (SEQ ID NO:24), FIG. 26 (SEQ ID NO:26), FIG. 28 (SEQ IDNO:28), FIG. 30 (SEQ ID NO:30), FIG. 32 (SEQ ID NO:32), FIG. 34 (SEQ IDNO:34), FIG. 36 (SEQ ID NO:36), FIG. 38 (SEQ ID NO:38), FIG. 40 (SEQ IDNO:40), FIG. 42 (SEQ ID NO:42), FIG. 44 (SEQ ID NO:44), FIG. 46 (SEQ IDNO:46), FIG. 48 (SEQ ID NO:48), FIG. 50 (SEQ ID NO:50), FIG. 52 (SEQ IDNO:52), FIG. 54 (SEQ ID NO:54), FIG. 56 (SEQ ID NO:56), FIG. 58 (SEQ IDNO:58), FIG. 60 (SEQ ID NO:60), FIG. 62 (SEQ ID NO:62), FIG. 64 (SEQ IDNO:64), FIG. 66 (SEQ ID NO:66), FIG. 68 (SEQ ID NO:68), FIG. 70 (SEQ IDNO:70), FIG. 72 (SEQ ID NO:72), FIG. 74 (SEQ ID NO:74), FIG. 76 (SEQ IDNO:76), FIG. 78 (SEQ ID NO:78), FIG. 80 (SEQ ID NO:80), FIG. 82 (SEQ IDNO:82), FIG. 84 (SEQ ID NO:84), FIG. 86 (SEQ ID NO:86), FIG. 88 (SEQ IDNO:88), FIG. 90 (SEQ ID NO:90), FIG. 92 (SEQ ID NO:92), FIG. 94 (SEQ IDNO:94), FIG. 96 (SEQ ID NO:96), FIG. 98 (SEQ ID NO:98), FIG. 100 (SEQ IDNO:100), FIG. 102 (SEQ ID NO:102), FIG. 104 (SEQ ID NO:104), FIG. 106(SEQ ID NO:106), FIG. 108 (SEQ ID NO:108), FIG. 110 (SEQ ID NO:110),FIG. 112 (SEQ ID NO:112) or FIG. 114 (SEQ ID NO:114), with itsassociated signal peptide; or (c) a nucleotide sequence encoding anextracellular domain of the polypeptide shown in FIG. 2 (SEQ ID NO:2),FIG. 4 (SEQ ID NO:4), FIG. 6 (SEQ ID NO:6), FIG. 8 (SEQ ID NO:8), FIG.10 (SEQ ID NO:10), FIG. 12 (SEQ ID NO:12), FIG. 14 (SEQ ID NO:14), FIG.16 (SEQ ID NO:16), FIG. 18 (SEQ ID NO:18), FIG. 20 (SEQ ID NO:20), FIG.22 (SEQ ID NO:22), FIG. 24 (SEQ ID NO:24), FIG. 26 (SEQ ID NO:26), FIG.28 (SEQ ID NO:28), FIG. 30 (SEQ ID NO:30), FIG. 32 (SEQ ID NO:32), FIG.34 (SEQ ID NO:34), FIG. 36 (SEQ ID NO:36), FIG. 38 (SEQ ID NO:38), FIG.40 (SEQ ID NO:40), FIG. 42 (SEQ ID NO:42), FIG. 44 (SEQ ID NO:44), FIG.46 (SEQ ID NO:46), FIG. 48 (SEQ ID NO:48), FIG. 50 (SEQ ID NO:50), FIG.52 (SEQ ID NO:52), FIG. 54 (SEQ ID NO:54), FIG. 56 (SEQ ID NO:56), FIG.58 (SEQ ID NO:58), FIG. 60 (SEQ ID NO:60), FIG. 62 (SEQ ID NO:62), FIG.64 (SEQ ID NO:64), FIG. 66 (SEQ ID NO:66), FIG. 68 (SEQ ID NO:68), FIG.70 (SEQ ID NO:70), FIG. 72 (SEQ ID NO:72), FIG. 74 (SEQ ID NO:74), FIG.76 (SEQ ID NO:76), FIG. 78 (SEQ ID NO:78), FIG. 80 (SEQ ID NO:80), FIG.82 (SEQ ID NO:82), FIG. 84 (SEQ ID NO:84), FIG. 86 (SEQ ID NO:86), FIG.88 (SEQ ID NO:88), FIG. 90 (SEQ ID NO:90), FIG. 92 (SEQ ID NO:92), FIG.94 (SEQ ID NO:94), FIG. 96 (SEQ ID NO:96), FIG. 98 (SEQ ID NO:98), FIG.100 (SEQ ID NO:100), FIG. 102 (SEQ ID NO:102), FIG. 104 (SEQ ID NO:104),FIG. 106 (SEQ ID NO:106), FIG. 108 (SEQ ID NO:108), FIG. 110 (SEQ IDNO:110), FIG. 112 (SEQ ID NO:112) or FIG. 114 (SEQ ID NO:114), lackingits associated signal peptide.
 19. An isolated polypeptide having atleast 80% amino acid sequence identity to: (a) an amino acid sequence ofthe polypeptide shown in FIG. 2 (SEQ ID NO:2), FIG. 4 (SEQ ID NO:4),FIG. 6 (SEQ ID NO:6), FIG. 8 (SEQ ID NO:8), FIG. 10 (SEQ ID NO:10), FIG.12 (SEQ ID NO:12), FIG. 14 (SEQ ID NO:14), FIG. 16 (SEQ ID NO:16), FIG.18 (SEQ ID NO:18), FIG. 20 (SEQ ID NO:20), FIG. 22 (SEQ ID NO:22), FIG.24 (SEQ ID NO:24), FIG. 26 (SEQ ID NO:26), FIG. 28 (SEQ ID NO:28), FIG.30 (SEQ ID NO:30), FIG. 32 (SEQ ID NO:32), FIG. 34 (SEQ ID NO:34), FIG.36 (SEQ ID NO:36), FIG. 38 (SEQ ID NO:38), FIG. 40 (SEQ ID NO:40), FIG.42 (SEQ ID NO:42), FIG. 44 (SEQ ID NO:44), FIG. 46 (SEQ ID NO:46), FIG.48 (SEQ ID NO:48), FIG. 50 (SEQ ID NO:50), FIG. 52 (SEQ ID NO:52), FIG.54 (SEQ ID NO:54), FIG. 56 (SEQ ID NO:56), FIG. 58 (SEQ ID NO:58), FIG.60 (SEQ ID NO:60), FIG. 62 (SEQ ID NO:62), FIG. 64 (SEQ ID NO:64), FIG.66 (SEQ ID NO:66), FIG. 68 (SEQ ID NO:68), FIG. 70 (SEQ ID NO:70), FIG.72 (SEQ ID NO:72), FIG. 74 (SEQ ID NO:74), FIG. 76 (SEQ ID NO:76), FIG.78 (SEQ ID NO:78), FIG. 80 (SEQ ID NO:80), FIG. 82 (SEQ ID NO:82), FIG.84 (SEQ ID NO:84), FIG. 86 (SEQ ID NO:86), FIG. 88 (SEQ ID NO:88), FIG.90 (SEQ ID NO:90), FIG. 92 (SEQ ID NO:92), FIG. 94 (SEQ ID NO:94), FIG.96 (SEQ ID NO:96), FIG. 98 (SEQ ID NO:98), FIG. 100 (SEQ ID NO:100),FIG. 102 (SEQ ID NO:102), FIG. 104 (SEQ ID NO:104), FIG. 106 (SEQ IDNO:106), FIG. 108 (SEQ ID NO:108), FIG. 110 (SEQ ID NO:110), FIG. 112(SEQ ID NO:112) or FIG. 114 (SEQ ID NO:114), lacking its associatedsignal peptide; (b) an amino acid sequence of an extracellular domain ofthe polypeptide shown in FIG. 2 (SEQ ID NO:2), FIG. 4 (SEQ ID NO:4),FIG. 6 (SEQ ID NO:6), FIG. 8 (SEQ ID NO:8), FIG. 10 (SEQ ID NO:10), FIG.12 (SEQ ID NO:12), FIG. 14 (SEQ ID NO:14), FIG. 16 (SEQ ID NO:16), FIG.18 (SEQ ID NO:18), FIG. 20 (SEQ ID NO:20), FIG. 22 (SEQ ID NO:22), FIG.24 (SEQ ID NO:24), FIG. 26 (SEQ ID NO:26), FIG. 28 (SEQ ID NO:28), FIG.30 (SEQ ID NO:30), FIG. 32 (SEQ ID NO:32), FIG. 34 (SEQ ID NO:34), FIG.36 (SEQ ID NO:36), FIG. 38 (SEQ ID NO:38), FIG. 40 (SEQ ID NO:40), FIG.42 (SEQ ID NO:42), FIG. 44 (SEQ ID NO:44), FIG. 46 (SEQ ID NO:46), FIG.48 (SEQ ID NO:48), FIG. 50 (SEQ ID NO:50), FIG. 52 (SEQ ID NO:52), FIG.54 (SEQ ID NO:54), FIG. 56 (SEQ ID NO:56), FIG. 58 (SEQ ID NO:58), FIG.60 (SEQ ID NO:60), FIG. 62 (SEQ ID NO:62), FIG. 64 (SEQ ID NO:64), FIG.66 (SEQ ID NO:66), FIG. 68 (SEQ ID NO:68), FIG. 70 (SEQ ID NO:70), FIG.72 (SEQ ID NO:72), FIG. 74 (SEQ ID NO:74), FIG. 76 (SEQ ID NO:76), FIG.78 (SEQ ID NO:78), FIG. 80 (SEQ ID NO:80), FIG. 82 (SEQ ID NO:82), FIG.84 (SEQ ID NO:84), FIG. 86 (SEQ ID NO:86), FIG. 88 (SEQ ID NO:88), FIG.90 (SEQ ID NO:90), FIG. 92 (SEQ ID NO:92), FIG. 94 (SEQ ID NO:94), FIG.96 (SEQ ID NO:96), FIG. 98 (SEQ ID NO:98), FIG. 100 (SEQ ID NO:100),FIG. 102 (SEQ ID NO:102), FIG. 104 (SEQ ID NO:104), FIG. 106 (SEQ IDNO:106), FIG. 108 (SEQ ID NO:108), FIG. 110 (SEQ ID NO:110), FIG. 112(SEQ ID NO:112) or FIG. 114 (SEQ ID NO:114), with its associated signalpeptide; or p1 (c) an amino acid sequence of an extracellular domain ofthe polypeptide shown in FIG. 2 (SEQ ID NO:2), FIG. 4 (SEQ ID NO:4),FIG. 6 (SEQ ID NO:6), FIG. 8 (SEQ ID NO:8), FIG. 10 (SEQ ID NO:10), FIG.12 (SEQ ID NO:12), FIG. 14 (SEQ ID NO:14), FIG. 16 (SEQ ID NO:16), FIG.18 (SEQ ID NO:18), FIG. 20 (SEQ ID NO:20), FIG. 22 (SEQ ID NO:22), FIG.24 (SEQ ID NO:24), FIG. 26 (SEQ ID NO:26), FIG. 28 (SEQ ID NO:28), FIG.30 (SEQ ID NO:30), FIG. 32 (SEQ ID NO:32), FIG. 34 (SEQ ID NO:34), FIG.36 (SEQ ID NO:36), FIG. 38 (SEQ ID NO:38), FIG. 40 (SEQ ID NO:40), FIG.42 (SEQ ID NO:42), FIG. 44 (SEQ ID NO:44), FIG. 46 (SEQ ID NO:46), FIG.48 (SEQ ID NO:48), FIG. 50 (SEQ ID NO:50), FIG. 52 (SEQ ID NO:52), FIG.54 (SEQ ID NO:54), FIG. 56 (SEQ ID NO:56), FIG. 58 (SEQ ID NO:58), FIG.60 (SEQ ID NO:60), FIG. 62 (SEQ ID NO:62), FIG. 64 (SEQ ID NO:64), FIG.66 (SEQ ID NO:66), FIG. 68 (SEQ ID NO:68), FIG. 70 (SEQ ID NO:70), FIG.72 (SEQ ID NO:72), FIG. 74 (SEQ ID NO:74), FIG. 76 (SEQ ID NO:76), FIG.78 (SEQ ID NO:78), FIG. 80 (SEQ ID NO:80), FIG. 82 (SEQ ID NO:82), FIG.84 (SEQ ID NO:84), FIG. 86 (SEQ ID NO:86), FIG. 88 (SEQ ID NO:88), FIG.90 (SEQ ID NO:90), FIG. 92 (SEQ ID NO:92), FIG. 94 (SEQ ID NO:94), FIG.96 (SEQ ID NO:96), FIG. 98 (SEQ ID NO:98), FIG. 100 (SEQ ID NO:100),FIG. 102 (SEQ ID NO:102), FIG. 104 (SEQ ID NO:104), FIG. 106 (SEQ IDNO:106), FIG. 108 (SEQ ID NO:108), FIG. 110 (SEQ ID NO:110), FIG. 112(SEQ ID NO:112) or FIG. 114 (SEQ ID NO:114), lacking its associatedsignal peptide.
 20. A method for stimulating the proliferation ordifferentiation of chondrocyte cells, said method comprising contactingsaid cells with a PRO6018 polypeptide, wherein the proliferation ordifferentiation of said cells is stimulated.
 21. A method forstimulating the proliferation of human microvascular endothelial cells,said method comprising contacting said cells with a PRO1313, PRO20080 orPRO21383 polypeptide, wherein the proliferation of said cells isstimulated.
 24. A method for inhibiting the proliferation of humanmicrovascular endothelial cells, said method comprising contacting saidcells with a PRO6071, PRO4487 or PRO6006 polypeptide, wherein theproliferation of said cells is inhibited.
 25. A method for detecting thepresence of tumor in a mammal, said method comprising comparing thelevel of expression of any PRO polypeptide shown in Table 8 in (a) atest sample of cells taken from said mammal and (b) a control sample ofnormal cells of the same cell type, wherein a higher level of expressionof said PRO polypeptide in the test sample as compared to the controlsample is indicative of the presence of tumor in said mammal.
 26. Themethod of claim 25, wherein said tumor is lung tumor, colon tumor,breast tumor, prostate tumor, rectal tumor, kidney tumor or liver tumor.27. A method for inducing endothelial cell tube formation comprisingadministering to the endothelial cell a PRO281, PRO1560, PRO189,PRO4499, PRO6308, PRO6000, PRO10275, PRO21207, PRO20933 or PRO34274polypeptide, or agonist thereof, wherein tube formation in saidendothelial cell is induced.
 28. An oligonucleotide probe derived fromany of the nucleotide sequences shown in the accompanying figures.